Composition and method for inhibiting platelet aggregation

ABSTRACT

The present invention provides novel compounds of dinucleotide polyphosphates and the method of preventing or treating diseases or conditions associated with platelet aggregation. The method comprises administering systemically to a patient a pharmaceutical comprising a purinergic P2 τ  receptor antagonist, in an amount effective to elevate its extracellular concentration to bind to P2 τ  receptors and inhibit P2 τ  receptor-mediated platelet aggregation. Methods of systemic administration include injection by intravenous, intramuscular, intrasternal and intravitreal routes, infusion, transdermal administration, oral administration, rectal administration and intra-operative instillation.

TECHNICAL FIELD

This invention relates to compounds of mono and dinucleotidepolyphosphates and the method of using such compounds in the preventionor treatment of diseases or conditions associated with plateletaggregation, including thrombosis in humans and other mammals.

BACKGROUND OF THE INVENTION

Hemostasis is the spontaneous process of stopping bleeding from damagedblood vessels. Precapillary vessels contract immediately when cut;within seconds, thrombocytes, or blood platelets, are bound to theexposed matrix of the injured vessel by a process called plateletadhesion. Platelets also stick to each other in a phenomenon known asplatelet aggregation to form a platelet plug to stop bleeding quickly.

An intravascular thrombus results from a pathological disturbance ofhemostasis. Platelet adhesion and aggregation are critical events inintravascular thrombosis. Activated under conditions of turbulent bloodflow in diseased vessels or by the release of mediators from othercirculating cells and damaged endothelial cells lining the vessel,platelets accumulate at a site of vessel injury and recruit furtherplatelets into the developing thrombus. The thrombus can grow tosufficient size to block off arterial blood vessels. Thrombi can alsoform in areas of stasis or slow blood flow in veins. Venous thrombi caneasily detach portions of themselves called emboli that travel throughthe circulatory system and can result in blockade of other vessels, suchas pulmonary arteries. Thus, arterial thrombi cause serious disease bylocal blockade, whereas venous thrombi do so primarily by distantblockade, or embolization. These conditions include venous thrombosis,thrombophlebitis, arterial embolism, coronary and cerebral arterialthrombosis, unstable angina, myocardial infarction, stroke, cerebralembolism, kidney embolisms and pulmonary embolisms.

A number of converging pathways lead to platelet aggregation. Whateverthe initial stimulus, the final common event is crosslinking ofplatelets by binding fibrinogen to a membrane binding site, glycoproteinIIb/IIIa (GPIIb/IIIa). Compounds that are antagonists for GPIIb/IIIareceptor complex have been shown to inhibit platelet aggregation (U.S.Pat. Nos. 6,037,343 and 6,040,317). Antibodies against GPIIb/IIIa havealso been shown to have high antiplatelet efficacy (The EPICinvestigators, New Engl. J. Med. (1994) 330:956-961). However, thisclass of antiplatelet agents sometimes causes bleeding problems.

Thrombin can produce platelet aggregation largely independently of otherpathways but substantial quantities of thrombin are unlikely to bepresent without prior activation of platelets by other mechanisms.Thrombin inhibitors such as hirudin are highly effective antithromboticagents. However, functioning as both antiplatelet and anti-coagulantagents, thrombin inhibitors again may produce excessive bleeding. (TheTIMI 9 a investigators, The GUSTO Iia investigators, Circulation, 90:1624-1630 (1994); Circulation, 90: 1631-1637 (1994); Neuhaus K. L. etal., Circulation, 90: 1638-1642 (1994))

Various antiplatelet agents have been studied for many years aspotential targets for inhibiting thrombus formation. Some agents such asaspirin and dipyridamole have come into use as prophylacticantithrombotic agents, and others have been the subjects of clinicalinvestigations. To date, the powerful agents such as disintegrins, andthe thienopyridines ticlopidine and clopidogrel have been shown to havesubstantial side effects, while agents such as aspirin have useful butlimited effectiveness (Hass, et al., N. Engl. J. Med., 321:501-507(1989); Weber, et al., Am. J. Cardiol. 66:1461-1468 (1990); Lekstrom andBell, Medicine 70:161-177 (1991)). In particular, use of thethienopyridines in antiplatelet therapy has been shown to increase theincidence of potentially life threatening thrombotic thrombocytopenicpurpura (Bennett, C.L. et al. N. Engl. J. Med, (2000) 342: 1771-1777).Aspirin, which has a beneficial effect on platelet aggregation (Br. Med.J. (1994) 308: 81-106; 159-168), acts by inducing blockade ofprostaglandin synthesis. Aspirin has no effect on ADP-induced plateletaggregation, and thus has limited effectiveness on platelet aggregation.Furthermore, its well documented high incidence of gastric side effectslimits its usefulness in many patients. Clinical efficacy of some newerdrugs, such as ReoPro (7E3), is impressive, but recent trials have foundthat these approaches are associated with an increased risk of majorbleeding, sometimes necessitating blood transfusion (New Engl. J. Med.(1994) 330:956-961). Thus it appears that the ideal “benefit/risk” ratiohas not been achieved.

Recent studies have suggested that adenosine 5′-diphosphate (ADP), acommon agonist, plays a key role in the initiation and progression ofarterial thrombus formation (Bernat, et al., Thromb. Haemostas. (1993)70:812-826); Maffrand, et al., Thromb. Haemostas. (1988) 59:225-230;Herbert, et al., Arterioscl. Thromb. (1993) 13:1171-1179). ADP inducesplatelet aggregation, shape change, secretion, influx and intracellularmobilization of Ca⁺², and inhibition of adenylyl cyclase. Binding of ADPto platelet receptors is required for elicitation of the ADP-inducedplatelet responses. There are at least three P2 receptors expressed inhuman platelets: a cation channel receptor P2X₁, a G protein-coupledreceptor P2Y₁, and a G protein-coupled receptor P2Y_(τ) , (also referredto as P2Y_(æ) and P2Y₁₂). The P2X₁ receptor is responsible for rapidcalcium influx and is activated by ATP and by ADP. However, its directrole in the process of platelet aggregation is unclear. The P2Y₁receptor is responsible for calcium mobilization, shape change and theinitiation of aggregation. P2Y_(τ) receptor is responsible forinhibition of adenylyl cyclase and is required for full aggregation.(Hourani, et al., The Platelet ADP Receptors Meeting, La Thuile, Italy,Mar. 29-31, 2000)

Ingall et al. (J. Med. Chem. 42: 213-220, (1999)) describe adose-related inhibition of ADP-induced platelet aggregation by analoguesof adenosine triphosphate (ATP), which is a weak, nonselective butcompetitive P2Y_(τ) receptor antagonist. Zamecnik (USPN 5,049,550)discloses a method for inhibiting platelet aggregation in a mammal byadministering to said mammal a diadenosine tetraphosphate compound ofApp(CH₂)ppA or its analogs. Kim et al. (USPN 5,681,823) disclose P¹,P⁴-dithio-P², P³-monochloromethylene 5′, 5″ diadenosine P¹,P⁴-tetraphosphate as an antithrombotic agent. The thienopyridinesticlopidine and clopidogrel, which are metabolized to antagonists of theplatelet P2Y_(τ) receptor, are shown to inhibit platelet function invivo (Quinn and Fitzgerald, Circulation 100:1667-1672 (1999); Geiger, etal., Arterioscler. Thromb. Vasc. Biol. 19:2007-2011 (1999)).

There is a need in the area of cardiovascular and cerebrovasculartherapeutics for an agent that can be used in the prevention andtreatment of thrombi, with minimal side effects, such as unwantedprolongation of bleeding in other parts of the circulation, whilepreventing or treating target thrombi. The inventors of the presentinvention have discovered new compounds that are antagonists of theeffect of ADP on its platelet membrane receptor, the P2Y_(τ) receptor.The compounds provide efficacy as antithrombotic agents by their abilityto block ADP from acting at its platelet receptor site and thus preventplatelet aggregation. Thus, these new compounds can provide a moreefficacious antithrombotic effect than aspirin, but with less profoundeffects on bleeding than antagonists of the fibrinogen receptor.Alternately, the compounds of the present invention can be used inconjunction with lower doses of these other agents which inhibitplatelet aggregation by different mechanisms, to reduce the toxicity ofthese agents. Finally, if the compounds of the present invention havesufficient binding affinity and bear a fluorescent moiety, they can finduses as biochemical probes for the P2_(τ) receptor.

SUMMARY OF THE INVENTION

The invention provides molecules whose structures fall within generalFormula I, and pharmaceutical formulations thereof. The invention alsoprovides compounds useful for the prevention of thrombosis. Accordingly,a broad embodiment of the invention relates to compounds of generalformula I, or salts thereof:

wherein:

-   -   X₁, X₂, and X₃ are independently or together oxygen, methylene,        monochloromethylene, dichloromethylene, monofluoromethylene,        difluoromethylene, or imido;    -   T, W, and V are independently to together oxygen or sulfur;    -   m=0,1 or 2;    -   n=0 or 1;    -   p=0,1, or 2;    -   where the sum of m+n+p is from 0 to 5;    -   M=hydrogen or a pharmaceutically-acceptable inorganic or organic        counterion;    -   D₁=O or C;    -   B′ is a purine or a pyrimidine residue according to general        formulas IV and V which is linked to the 1′ position of the        furanose or carbocycle via the 9- or 1-position, respectively;    -   Y′=hydrogen or OR₁;    -   Z′=hydrogen or OR₂;    -   A=M, alkyl, cycloalkyl, aralkyl, aryl, or acylthioalkyl, with or        without substituents or    -   heteroatoms; or    -   A is a nucleoside residue which is defined as:        and which is linked to the phosphate chain via the 5′ position        of the furanose or carbocycle; wherein:    -   D₂=O or C;    -   Z=hydrogen or OR₃;    -   Y=hydrogen or OR₄;    -   B is a purine or a pyrimidine residue according to general        formulas IV and V which is linked to the furanose or carbocycle        via the 9- or 1-position, respectively;    -   R₁, R₂, R₃, and R₄ can be H, provided that at least one of the        four is a residue according to general formulas II and III which        is linked to the 2′ or 3′ furanose or carbocycle hydroxyl oxygen        via a carbon atom.    -   When D₁ and D₂ are oxygen, the furanosyl moieties are in the        D-configuration, but may be L-, or D- and L-. The        D-configuration is preferred.

The invention also provides pharmaceutical compositions comprisingcompounds of Formula I, which are highly selective antagonists of P_(2τ)receptor on platelets. The invention further provides a method ofpreventing or treating diseases or conditions associated with plateletaggregation; such diseases include venous thrombosis, thrombophlebitis,arterial embolism, coronary and cerebral arterial thrombosis, unstableangina, myocardial infarction, stroke, cerebral embolism, kidneyembolisms and pulmonary embolisms. The method comprises administering toa patient a pharmaceutical composition comprising a compound of FormulaI in an amount effective to bind to the P_(2τ) receptors on plateletsand inhibit ADP-induced platelet aggregation.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides molecules which fall within the scope of generalFormula I, and pharmaceutically acceptable salts thereof. Accordingly, abroad embodiment of the invention relates to compounds of generalformula I, or salts thereof:

wherein:

-   -   X₁, X₂, and X₃ are independently or together oxygen, methylene,        monochloromethylene, dichloromethylene, monofluoromethylene,        difluoromethylene, or imido;    -   T, W, and V are independently or together oxygen or sulfur;    -   m=0, 1 or 2;    -   n=0 or 1;    -   p=0, 1, or 2;    -   where the sum of m+n+p is from 0 to 5;    -   M=H or a pharmaceutically-acceptable inorganic or organic        counterion;    -   D₁=O or C;    -   B′ is a purine or a pyrimidine residue according to general        formulas IV and V which is linked to the 1′ position of the        furanose or carbocycle via the 9- or 1- position, respectively;    -   Y′=H or OR₁;    -   Z′=H or OR₂;    -   A=M, alkyl, cycloalkyl, aralkyl, aryl, or acylthioalkyl, with or        without substituents or heteroatoms; or    -   A is a nucleoside residue which is defined as:        and which is linked to the phosphate chain via the 5′ position        of the furanose or carbocycle;    -   wherein:    -   Z=H or OR₃;    -   Y=H or OR₄;    -   D₂=O or C;    -   B is a purine or a pyrimidine residue according to general        formulas IV and V which is linked to the sugar via the 9- or        1-position, respectively;    -   R₁, R₂, R₃, and R₄ can be H, provided that at least one of the        four is a residue according to general formulas II and III which        is linked to the 2′ or 3′ furanose or carbocycle hydroxyl oxygen        via a carbon atom;    -   Further provisions are that when D₁ and D₂ are oxygen, the        furanose is preferably in the β-configuration;        and that the furanose is most preferably in the        β-D-configuration.

Preferred compounds of general Formula I are molecules whose structuresfall within the definitions of Formula Ia and Formula Ib:

wherein:

-   -   X₁, X₂, and X₃=O;    -   T, V, and W=O;    -   M=H, NH₄ ^(±), Na⁺ or other pharmaceutically-acceptable        inorganic or organic counterion;    -   Y′=H, OH, or OR₁, where OR₁ falls under the definition of        general formula II;    -   Z′=OH or OR₂, where OR₂ falls under the definition of general        formula II;    -   Z=OH or OR₃, where OR₃ falls under the definition of general        formula II;    -   Y=H, OH, or OR₄, where OR₄ falls under the definition of general        formula II;    -   D₁=O;    -   D₂=O or C;    -   B and B′ are purine or pyrimidine residues according to general        formulas IV and V;    -   m and p=0,1 or 2;    -   n=0 or 1;    -   such that the sum of m+n+p is from 0 to 5; or    -   X₁, X₂, and X₃=O;    -   T, V, and W=O;    -   M=H, NH₄ ^(±), Na⁺ or other pharmaceutically-acceptable        inorganic or organic counterion;    -   Y′=H, OH, or OR₁, where OR₁ falls under the definition of        general formula III;    -   Z′=OH or OR₂, where OR₂ falls under the definition of general        formula III;    -   Z=OH or OR₃, where OR₃ falls under the definition of general        formula III;    -   Y=H, OH, or OR₄, where OR₄ falls under the definition of general        formula III;    -   D₁=O;    -   D₂=O or C;    -   B and B′ are purine or pyrimidine residues according to general        formulas IV and V;    -   m and p=0,1 or 2;    -   n=0 or 1;    -   such that the sum of m=n=p is from 0 to 5; or    -   X₁ and X₃=O;    -   X₂=methylene, monochloromethylene, dichloromethylene,        monofluoromethylene, difluoromethylene, or imido;    -   T, V, and W=O;    -   M=H, NH₄ ^(±), Na⁺ or other pharmaceutically-acceptable        inorganic or organic counterion;    -   Y′=H, OH, or OR₁, where OR₁ falls under the definition of        general formula II;    -   Z′=OH or OR₂, where OR₂ falls under the definition of general        formula II;    -   Z=OH or OR₃, where OR₃ falls under the definition of general        formula II;    -   Y=H, OH, or OR₄, where OR₄ falls under the definition of general        formula II;    -   D₁=O;    -   D₂=O or C;    -   B and B′ are purine or pyrimidine residues according to general        formulas IV and V;    -   m and p=0,1 or 2;    -   n=1;    -   such that the sum of m=n=p is from 1 to 5; or    -   X₁ and X₃=O;    -   X₂=methylene, monochloromethylene, dichloromethylene,        monofluoromethylene, difluoromethylene, or imido;    -   T, V, and W=O;    -   M=H, NH₄ ^(±), Na⁺ or other pharmaceutically-acceptable        inorganic or organic counterion;    -   Y′=H, OH, or OR₁, where OR₁ falls under the definition of        general formula III;    -   Z′=OH or OR₂, where OR₂ falls under the definition of general        formula III;    -   Z=OH or OR₃, where OR₃ falls under the definition of general        formula III;    -   Y=H, OH, or OR₄, where OR₄ falls under the definition of general        formula III;    -   D₁=O;    -   D₂=O or C;    -   B and B′ are purine or pyrimidine residues according to general        formulas IV and V;    -   m and p=0,1 or 2;    -   n=1;    -   such that the sum of m+n+p is from 1 to 5; or    -   X₁ and X₃=O;    -   X₂=methylene, monochloromethylene, dichloromethylene,        monofluoromethylene, difluoromethylene, or imido;    -   T=S;    -   V and W=O;    -   M=H, NH₄ ^(±), Na⁺ or other pharmaceutically-acceptable        inorganic or organic counterion;    -   Y′=H, OH, or OR₁, where OR₁ falls under the definition of        general formula II;    -   Z′=OH or OR₂, where OR₂ falls under the definition of general        formula II;    -   Z=OH or OR₃, where OR₃ falls under the definition of general        formula II;    -   Y=H, OH, or OR₄, where OR₄ falls under the definition of general        formula II;    -   D₁=O;    -   D₂=O or C;    -   B and B′ are purine or pyrimidine residues according to general        formulas IV and V;    -   m, n, and p=1; or    -   X₁ and X₃=O;    -   X₂=methylene, monochloromethylene, dichloromethylene,        monofluoromethylene, difluoromethylene, or imido;    -   T=S;    -   V and W=O;    -   M=H, NH₄ ^(±), Na⁺ or other pharmaceutically-acceptable        inorganic or organic counterion;    -   Y′=H, OH, or OR₁, where OR₁ falls under the definition of        general formula III;    -   Z′=OH or OR₂, where OR₂ falls under the definition of general        formula III;    -   Z=OH or OR₃, where OR₃ falls under the definition of general        formula III;    -   Y=H, OH or OR₄, where OR₄ falls under the definition of general        formula III;    -   D₁=O;    -   D₂=O or C;    -   B and B′ are purine or pyrimidine residues according to general        formulas IV and V;    -   m, n, and p=1; or        where for general formula I, m=0, and all other definitions        remain the same;    -   wherein:    -   A=M, alkyl, cycloalkyl, aralkyl, aryl, or acylthioalkyl, with or        without substituents or heteroatoms;    -   X₁ and X₂=O;    -   T, V, and W=O;    -   M=H, NH₄ ^(±), Na⁺ or other pharmaceutically-acceptable        inorganic or organic counterion;    -   Y′=H, OH, or OR₁, where OR₁ falls under the definition of        general formula II;    -   Z′=OH or OR₂, where OR₂ falls under the definition of general        formula II;    -   With the provision that at least one of Y′ and Z′ is OR₁ or OR₂;    -   D₁=O or C;    -   B′ is purine or pyrimidine residue according to general formulas        IV and V;    -   n and p=0.1, or 2 such that the sum of n+p is from 0 to 3; or    -   A=M, alkyl, cycloalkyl, aralkyl, aryl, or acylthioalkyl, with or        without substituents or heteroatoms;    -   X₁ and X₂=O;    -   T, V, and W=O;    -   M=H, NH₄ ^(±), Na⁺ or other pharmaceutically-acceptable        inorganic or organic counterion;    -   Y′=OR₁, where OR₁ falls under the definition of general formula        III;    -   Z′=OR₂, where OR₂ falls under the definition of general formula        III;    -   D₁=O or C;    -   B′ is purine or pyrimidine residue according to general formulas        IV and V;    -   n and p=0,1, or 2 such that the sum of n=p is from 0 to 3; or    -   A=M, alkyl, cycloalkyl, aralkyl, aryl, or acylthioalkyl, with or        without substituents or heteroatoms;    -   X₁ and X₂=O;    -   T and V=O;    -   W=S;    -   M=H, NH₄ ^(±), Na⁺ or other pharmaceutically-acceptable        inorganic or organic counterion;    -   Y′=H, OH, or OR₁, where OR₁ falls under the definition of        general formula II;    -   Z′=OH or OR₂, where OR₂ falls under the definition of general        formula II;    -   With the provision that at least one of Y′ and Z′ is OR₁ or OR₂;    -   D₁=O or C;    -   B′ is purine or pyrimidine residue according to general formulas        IV and V;    -   p=0,1, or 2 such that the sum of n+p is from 1 to 3;    -   n=1; or    -   A=M, alkyl, cycloalkyl, aralkyl, aryl, or acylthioalkyl, with or        without substituents or heteroatoms;    -   X₁ and X₂=O;    -   T and V=O;    -   W=S;    -   M=H, NH₄ ^(±), Na⁺ or other pharmaceutically-acceptable        inorganic or organic counterion;    -   Y′=OR₁, where OR₁ falls under the definition of general formula        III;    -   Z′=OR₂, where OR₂ falls under the definition of general formula        III;    -   D₁=O or C;    -   B′is purine or pyrimidine residue according to general formulas        IV and V;    -   p=0,1, or 2 such that the sum of n+p is from 1 to 3;    -   n=1; or    -   A=M, alkyl, cycloalkyl, aralkyl, aryl, or acylthioalkyl, with or        without substituents or heteroatoms;    -   X₁=O;    -   X₂=methylene, monochloromethylene, dichloromethylene,        monofluoromethylene, difluoromethylene, imido;    -   T, V, and W=O;    -   M=H, NH₄ ^(±), Na⁺ or other pharmaceutically-acceptable        inorganic or organic counterion;    -   Y′=H, OH, or OR₁, where OR₁ falls under the definition of        general formula II;    -   Z′=H, OH or OR₂, where OR₂ falls under the definition of general        formula II;    -   With the provision that at least one of Y′ and Z′ is OR₁ or OR₂;    -   D₁=O or C;    -   B′ is purine or pyrimidine residue according to general formulas        IV and V;    -   p=0, 1, or 2 such that the sum of n+p is from 1 to 3;    -   n=1; or    -   A=M, alkyl, cycloalkyl, aralkyl, aryl, or acylthioalkyl, with or        without substituents or heteroatoms;    -   X₁=O;    -   X₂=methylene, monochloromethylene, dichloromethylene,        monofluoromethylene, difluoromethylene, or imido;    -   T, V, and W=O;    -   M=H, NH₄ ^(±), Na⁺ or other pharmaceutically-acceptable        inorganic or organic counterion;    -   Y′=H, OH, or OR₁, where OR₁ falls under the definition of        general formula III;    -   Z′=H, OH or OR₂, where OR₂ falls under the definition of general        formula III;    -   D₁=O or C;    -   B′ is purine or pyrimidine residue according to general formulas        IV and V;    -   p=0, 1, or 2 such that the sum of n+p is from 1 to 3;    -   n=1; or

For compounds according to formula Ia or Ib, where Y′=OR₁, Z′=OR₂, Z=OR₃and/or Y= OR₄, at least one of the four must be a residue which islinked directly to the corresponding 2′ or 3′ hydroxyl oxygen of thefuranose or carbocycle via a carbon atom. For the most part, thisresidue falls within the scope of formula II or formula III:

wherein:

-   -   O is the corresponding 2′ and/or 3′ oxygen of the furanose or        carbocycle;    -   Q is a carbon atom;    -   R₅, R₆, and R₇ are H, an alkyl, cycloalkyl, aralkyl, aryl,        substituted aralkyl, or substituted aryl, such that the moiety        defined according to formula II is an ether; or    -   provided that R₅ and R₆ are taken together to mean oxygen or        sulfur doubly bonded to Q, and R₇ is alkyl, cycloalkyl, aralkyl,        aryl, substituted aralkyl, or substituted aryl, such that the        moiety defined according to formula II is an ester or thioester;        or    -   provided that R₅ and R₆ are taken together to mean oxygen or        sulfur doubly bonded to Q, and R₇ is amino or mono- or        disubstituted amino, where the substituents are alkyl,        cycloalkyl, aralkyl, aryl, substituted aralkyl, or substituted        aryl, such that the moiety according to formula II is a        carbamate or thiocarbamate; or    -   provided that R₅ and R₆ are taken together to mean oxygen or        sulfur doubly bonded to Q, and R₇ is alkoxy, cycloalkoxy,        aralkyloxy, aryloxy, substituted aralkyloxy, or substituted        aryloxy, such that the moiety according to formula II is a        carbonate or thiocarbonate; or    -   provided that R₅ and R₆ are taken together to mean oxygen or        sulfur doubly bonded to Q and both the 2′ and 3′ oxygens of the        furanose are directly bound to Q to form a cyclical carbonate or        thiocarbonate, R₇ is not present; or        wherein:    -   O is the 2′ and 3′ oxygens of the furanose or carbocycle; and    -   the 2′ and 3′ oxygens of the furanose or carbocycle are linked        by a common carbon atom to form a cyclical acetal, cyclical        ketal, or cyclical orthoester; and    -   for cyclical acetals and ketals, R₈ and R₉ are independently        hydrogen, alkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl,        substituted aryl, or may be joined together to form a homocyclic        or heterocyclic ring composed of 3 to 8 atoms, or    -   for cyclical orthoesters, R₈ is hydrogen, alkyl, cycloalkyl,        aralkyl, aryl, substituted aralkyl, or substituted aryl,    -   and R₉ is alkyloxy, cycloalkyloxy, aralkyloxy, aryloxy,        substituted aralkyloxy, or substituted aryloxy.

In general,R₅ to R₉ may be defined as, but are not limited to, thefollowing:

-   -   Alkyl groups are from 1 to 8 carbons, either straight chained or        branched, with or without unsaturation and with or without        heteroatoms;    -   Cycloalkyl groups are from 3 to 8 carbons, with or without        unsaturation, and with or without heteroatoms;    -   Aralkyl groups are from 1 to 5 carbons in the alkyl portion, and        are monocyclic or polycyclic moieties from 4 to 8 carbons per        ring, with or without heteroatoms, in the aryl portion;    -   Aryl groups are monocyclic or polycyclic moieties from 4 to 8        carbons, with or without heteroatoms; and these groups may or        may not bear substituents.

Preferred substituents on the foregoing groups may be, but are notlimited to, hydroxy, nitro, methoxy, fluoro, chloro, bromo, iodo,methyl, ethyl, propyl, butyl, thioalkyl, alkoxy, carboxyl, cyano, amino,substituted amino, trifluoromethyl, phenyl, cyclopropyl, cyclopentyl,and cyclohexyl; and

Preferred heteroatoms are oxygen, nitrogen, and sulfur.

B and B′ are independently a purine residue, as in formula IV, linkedthrough the 9-position, or a pyrimidine residue, as in formula V, linkedthrough the 1-position. The ribosyl moieties are in the D-configuration,as shown, but may be L-, or D- and L-. The D-configuration is preferred.

wherein:

-   -   R₁₀ and R₁₄ are hydroxy, oxo, amino, mercapto, alkylthio,        alkyloxy, aryloxy, alkylamino, cycloalkylamino, aralkylamino,        arylamino, diaralkylamino, diarylamino, or dialkylamino, where        the alkyl groups are optionally linked to form a heterocycle; or    -   R₁₀ and R₁₄ are acylamino, provided that they incorporate an        amino residue from the C-6 position of the purine or the C-4        position of the pyrimidine; or    -   when R₁₀ in a purine or R₁₄ in a pyrimidine has as its first        atom nitrogen, R₁₀ and R₁₁ or R₁₄ and R₁₅ are taken together to        form a 5-membered fused imidazole ring (etheno compounds),        optionally substituted on the etheno ring with alkyl,        cycloalkyl, aralkyl, or aryl moieties, as described for R₅-R₉        above;    -   J is carbon or nitrogen, with the provision that when nitrogen,        R12 is not present;    -   R₁₁ hydrogen, O (adenine 1-oxide derivatives) or is absent        (adenine derivatives);    -   R₁₅ hydrogen, or acyl (e.g. acetyl, benzoyl, phenylacyl, with or        without substituents); or    -   R₁₂ hydrogen, alkyl, azido, alkylamino, arylamino or        aralkylamino, alkoxy, aryloxy or aralkyloxy, alkylthio, arythio        or aralkylthio, or ω-A(C₁₋₆alkyl)B- wherein A and B are        independently amino, mercapto, hydroxy or carboxyl;    -   R₁₃ is hydrogen, chlorine, amino, monosubstituted amino,        disubstituted amino, alkylthio, arylthio, or aralkylthio, where        the substituent on sulfur contains up to a maximum of 20 carbon        atoms, with or without unsaturation;    -   R₁₆ is hydrogen, methyl, alkyl, halo, alkyl, alkenyl,        substituted alkenyl, alkynyl, or substituted alkynyl;    -   Compounds according to formulas IV and V where R₁₀ or R₁₄ is        acylamino for the most part fall within the scope of formula VI:        wherein:    -   NH is the amino residue at the C-6 position in a purine or the        amino residue at the C-4 position in a pyrimidine;    -   Q is a carbon atom;    -   W is oxygen or sulfur;    -   R₁₇ is amino or mono- or disubstituted amino such that the        moiety according to formula VI is a urea or thiourea; or    -   R₁₇ is alkoxy, aralkyloxy, aryloxy, substituted aralkyloxy, or        substituted aryloxy, such that the moiety according to formula        VI is a carbamate or thiocarbamate; or    -   R₁₇ is alkyl, cycloalkyl, aralkyl, or aryl, with or without        substituents or heteroatoms, such that the moiety according to        formula VI is an amide.

The compounds of the present invention may be conveniently synthesizedby those skilled in the art using well-known chemical procedures.Mononucloside mono-, di- and triphosphates may be obtained fromcommercial sources or may be synthesized from the nucleoside using avariety of phosphorylation reactions which may be found in the chemicalliterature. Symmetrical and unsymmetrical dinucleotide polyphosphatesmay be prepared by activation of a nucleoside mono-, di- or triphosphatewith a coupling agent such as, but not limited to,dicyclohexylcarbodiimide or 1, 1′-carbonyldiimidazole, followed bycondensation with another nucleoside mono-, di-, or triphosphate, whichmay be the same or different as the activated moiety. Activation ofnucleoside triphosphates with dicyclohexylcarbodiimide gives a cyclicaltrimetaphosphate as the activated species, which may be advantageouslyreacted with a variety of nucleophiles to install unique substituents onthe terminal phosphate of a triphosphate.

The compounds of the present invention may be prepared by derivatizationor substitution at the level of the nucleoside, followed byphosphorylation and condensation as previously described, or thereactions may be carried out directly on the preformed mono- ordinucleotides. In the general formulas Ia and Ib, the substituents atY′, Z′, Y, and Z may be esters, carbamates, or carbonates, which aregenerally described by formula II. Esters may be readily prepared byreacting a hydroxyl group of the furanose in a nucleoside or nucleotidewith an activated form of an appropriate organic acid, such as an acidhalide or acid anhydride in the presence of an organic or inorganicbase. Alternately, use of a suitable coupling reagent such asdicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole and the like toactivate the organic acid may be used to achieve the same result.

Carbamates or thiocarbamates may be most conveniently prepared byreaction of a hydroxyl group of the furanose in a nucleoside ornucleotide with any of a number of commercially available isocyanates orisothiocyanates, respectively, in an inert solvent. Alternately, when adesired isocyanate or isothiocyanate cannot be obtained from commercialsources, they may be prepared from the corresponding amine by the use ofphosgene or thiophosgene, respectively, or their chemical equivalents.Carbonates or thiocarbonates may be synthesized by reacting the hydroxylgroups of a furanose in a nucleoside or nucleotide with an appropriatehaloformate in the presence of an organic or inorganic base.

In the general formulas Ia and Ib, the substituents at Y′and Z′, and Yand Z, when taken together, may be taken to mean acetals, ketals ororthoesters, as described in formula III. Acetals and ketals may bereadily prepared by reaction of the neighboring 2′ and 3′ hydroxylgroups of the furanose in an appropriate nucleoside or nucleotide withan aldehyde or ketone, respectively, or their chemical equivalents, inthe presence of an acid catalyst. Particularly advantageous is the useof an organic acid, which can effect the transformation withoutaffecting the integrity of the rest of the molecule. Alternately, strongacids such as trichloroacetic, p-toluenesulfonic, methanesulfonic andthe like may be employed in catalytic amounts, in conjunction with inertsolvents. Most preferred is formic acid, which is ideally suited toserve as both solvent and catalyst for these reactions. The discovery ofthe utility of formic acid for this purpose is one particular aspect ofthis invention.

Cyclical orthoesters may be prepared by reaction of the neighboring 2′and 3′ hydroxyl groups of a furanose with an acyclic orthoester, in thepresence of an acid. When the nucleoside or nucleotide to be derivatizedis a purine that contains a 6-amino functionality or is a pyrimidinethat contains a 4-amino functionality, it may be converted to therespective urea or thiourea by treatment with isocyanates orisothiocyanates, respectively, as was previously described forcarbamates or thiocarbamates of the 2′ or 3′ hydroxyls of the furanose.It was found that reactions of the amino group with isocyanates orisothiocyanates could be carried out in the presence of the hydroxylgroups of the furanose, by appropriate manipulation of the stoichiometryof the reaction.

All of the derivitization reactions described may be carried out onpreformed dinucleotide polyphosphates, which results in multipleproducts dependent of reaction stoichiometry and on whether multiplereactive groups are present. When multiple products are obtained, thesemay be conveniently separated by the use of preparative reverse phasehigh performance liquid chromatography (HPLC). Particularly advantageousis the use of C18 or phenyl reverse phase columns, in conjunction withgradients that start with ammonium acetate buffer and end with methanol.The use of a buffer provides for nucleotide stability and improved peakshape of the eluting products and the use of methanol allows foreffective desorption of these lipophilic compounds from the column.Particularly advantageous is the use of ammonium acetate buffersolutions in conjunction with methanol, as these solvents are misciblein all proportions and may be readily removed from the chromatographedproducts by evaporation, followed by lyophilization.

While separation of multiple products may be done by HPLC, anotherstrategy is to use nucleosides or nucleotides which contain only asingle reactive functionality, whether because only one is present, orby the use of protecting groups to block side reactions at otherpositions in the molecule. This may be done at the level of preformeddinucleotide polyphosphates, or alternately, may be carried out onnucleoside mono-, di-, or triphosphates, leading to novel products intheir own right, or may be coupled to other nucleoside mono-, di-, ortriphosphates by the methods which have already been described.

The novel compounds of the present invention are useful in therapy, inparticular in the prevention of platelet aggregation. The compounds ofthe present invention are thus useful as anti-thrombotic agents, and arethus useful in the treatment or prevention of unstable angina, coronaryangioplasty (PTCA) and myocardial infarction.

The compounds of the present invention are also useful in the treatmentor prevention of primary arterial thrombotic complications ofatherosclerosis such as thrombotic stroke, peripheral vascular disease,myocardial infarction without thrombolysis.

Still further indications where the compounds of the invention areuseful are for the treatment or prevention of arterial thromboticcomplications due to interventions in atherosclerotic disease such asangioplasty, endarterectomy, stent placement, coronary and othervascular graft surgery.

Still further indications where the compounds of the invention areuseful are for the treatment or prevention of thrombotic complicationsof surgical or mechanical damage such as tissue salvage followingsurgical or accidental trauma, reconstructive surgery including skinflaps, and “reductive” surgery such as breast reduction.

The compounds of the present invention are also useful for theprevention of mechanically-induced platelet activation in vivo such ascardiopulmonary bypass (prevention of microthromboembolism), preventionof mechanically-induced platelet activation in vitro such as the use ofthe compounds in the preservation of blood products, e.g. plateletconcentrates, prevention of shunt occlusion such as renal dialysis andplasmapheresis, thrombosis secondary to vascular damage/inflammationsuch as vasculities, arteritis, glomerulonephritis and organ graftrejection.

Still further indications where the compounds of the present inventionare useful are indications with a diffuse thrombotic/plateletconsumption component such as disseminated intravascular coagulation,thrombotic thrombocytopenic purpura, hemolytic uremic syndrome,heparin-induced thrombocytopenia and pre-eclampsia/eclampsia.

Still further indications where the compounds of the invention areuseful are for the treatment or prevention of venous thrombosis such asdeep vein thrombosis, veno-occlusive disease, hematological conditionssuch as thrombocythemia and polycythemia, and migraine.

In a particularly preferred embodiment of the present invention, thecompounds are used in the treatment of unstable angina, coronaryangioplasty and myocardial infarction.

In another particularly preferred embodiment of the present invention,the compounds are useful as adjunctive therapy in the prevention ofcoronary arterial thrombosis during the management of unstable angina,coronary angioplasty and acute myocardial infarction, i.e.perithrombolysis. Agents commonly used for adjunctive therapy in thetreatment of thrombotic disorders may be used, for example heparinand/or aspirin, just to mention a few.

A method of treating a mammal to alleviate the pathological effects ofatherosclerosis and arteriosclerosis, acute MI, chronic stable angina,unstable angina, transient ischemic attacks and strokes, peripheralvascular disease, arterial thrombosis, preeclampsia, embolism,restenosis or abrupt closure following angioplasty, carotidendarterectomy, and anastomosis of vascular grafts.

The compounds of this invention may be used in vitro to inhibit theaggregation of platelets in blood and blood products, e.g. for storage,or for ex vivo manipulations such as in diagnostic or research use. Thisinvention also provides a method of inhibiting platelet aggregation andclot formation in a mammal, especially a human, which comprises theinternal administration of a compound of formula (I) and apharmaceutically acceptable carrier.

Chronic or acute states of hyper-aggregability, such as disseminatedintravascular coagulation (DIC), septicemia, surgical or infectiousshock, post-operative and post-partum trauma, cardiopulmonary bypasssurgery, incompatible blood transfusion, abruptio placenta, thromboticthrombocytopenic purpura (TTP), snake venom and immune diseases, arelikely to be responsive to such treatment. In addition, the compounds ofthis invention may be useful in a method for the prevention ofmetastatic conditions, the prevention or treatment of fungal orbacterial infection, inducing immunostimulation, treatment of sicklecell disease, and the prevention or treatment of diseases in which boneresorption is a factor.

This invention further provides a method for inhibiting the reocclusionof an artery or vein following fibrinolytic therapy, which comprisesinternal administration of a compound of formula (I) and a fibrinolyticagent. When used in the context of this invention, the term fibrinolyticagent is intended to mean any compound, whether a natural or syntheticproduct, which directly or indirectly causes the lysis of a fibrin clot.Plasminogen activators are a well known group of fibrinolytic agents.Useful plasminogen activators include, for example, anistreplase,urokinase (UK), pro-urokinase (pUK), streptokinase (SK), tissueplasminogen activator (tPA) and mutants, or variants thereof, whichretain plasminogen activator activity, such as variants which have beenchemically modified or in which one or more amino acids have been added,deleted or substituted or in which one or more functional domains havebeen added, deleted or altered such as by combining the active site ofone plasminogen activator or fibrin binding domain of anotherplasminogen activator or fibrin binding molecule.

Extracorporeal circulation is routinely used for cardiovascular surgeryin order to oxygenate blood. Platelets adhere to surfaces of theextracorporeal circuit. Platelets released from artificial surfaces showimpaired hemostatic function. Compounds of the invention may beadministered to prevent adhesion.

Other applications of these compounds include prevention of plateletthrombosis, thromboembolism and reocclusion during and afterthrombolytic therapy and prevention of platelet thrombosis,thromboembolism and reocclusion after angioplasty of coronary and otherarteries and after coronary artery bypass procedures.

The compounds of the present invention also encompass their non-toxicpharmaceutically acceptable salts, such as, but not limited to, analkali metal salt such as sodium or potassium; an alkaline earth metalsalt such as manganese, magnesium or calcium; or an ammonium ortetraalkyl ammonium salt, i.e., NX₄ ⁺ (wherein X is C¹⁻⁴).Pharmaceutically acceptable salts are salts that retain the desiredbiological activity of the parent compound and do not impart undesiredtoxicological effects.

EXAMPLE 1 2′(3′)-O-((phenylaminocarbonyl)-uridine 5′-)triphosphate

Uridine 5″-triphosphate, ditributylammonium salt (100 mg, 0.176 mmol;prepared from the trisodium salt by treatment with Dowex 50W×4 H⁺ inwater, followed by mixing the protonated species with an excess oftributylamine, stripping and lyophilization) was dissolved in dry DMF (1mL) and phenylisocyanate (19 uL, 0.176 mmol) added. The reaction mixturewas heated at 45° C. for 15 minutes, at which point a further portion ofphenylisocyanate (19 uL, 0.176 mmol) was added. The solution was heatedat 45° C. overnight and the DMF was removed on a rotary evaporator. Theresidual oil was partitioned between water (2 mL) and ethyl acetate (2mL) and the layers were separated. The aqueous layer was extracted twicemore with ethyl acetate (2 mL each) and the water was removed on arotary evaporator. The residue was dissolved in water (1.5 mL) and theproduct isolated by repeated injections onto a preparative HPLC column(Alltech Nucleotide/Nucleoside C18, 7 um, 10 X 250 mm, gradient from 0.1M ammonium acetate to methanol over 30 minutes, 5 mL/min, monitor at 260nm). The yield of the carbamate was 26 mg (22%, calculated for thetetraammonium salt). 1H NMR showed the product to be a mixture of 2′ and3′ carbamates. The product so obtained can be used for the purposes ofthis invention per se or can be activated with a suitable coupling agent(e.g. a carbodiimide) and reacted with a variety of nucleotides togenerate novel dinucleoside polyphosphates, or with non-nucleotidenucleophiles to give nucleotides bearing novel moieties on the terminalphosphate.

1H NMR (D2O, 300 MHz): δ 4.10-4.47 (m, 4H), 5.17 (m, 1H), 5.83 (dd, 1H),5.96 (m, 1H), 7.04 (t, 1H), 7.25 (m, 4H), 7.79 (m, 1H). 31P NMR(D2O,121.47 MHz): δ -9.54 (m, 1P), -10.20 (m, 1P), -21.87 (m, 1P).

EXAMPLE 2 2′(3′)-O-(phenylaminocarbonyl)-P¹,P⁴-Di(uridine5′-)tetraphosphate and P¹,P⁴-Di-(2′(3′)-O-(phenylaminocarbonyl)uridine5′-)tetraphosphate

P¹,P⁴-Di(uridine 5′-) tetraphosphate, ditributylammonium salt (211 mg,0.182 mmol; prepared from the tetrasodium salt by treatment with Dowex50W×4 H⁺ in water, followed by mixing the protonated species with anexcess of tributylamine, stripping and lyophilization) was dissolved indry DMF (2 mL) and phenylisocyanate (40 uL, 3.64 mmol) added in a singleportion. The homogeneous reaction mixture was heated overnight at 45°C., whereupon TLC (silica gel, 50% isopropanol/50% ammonium hydroxide)indicated a substantial conversion to two products. The solvent wasremoved on a rotary evaporator and the residue was partitioned betweenwater (7 mL) and ethyl acetate (10 mL). The layers were separated, andthe aqueous was extracted twice more with ethyl acetate. (10 mL each).The water was removed from the aqueous extract and the residual oillyophilized overnight. The solid obtained was reconstituted in water (3mL) and the two products separated by repeated injections onto asemipreparative HPLC column (Alltech Nucleotide/Nucleoside C18, 7 um, 10X 250 mm, gradient from 0.1 M ammonium acetate to methanol over 30minutes, 5 mL/min, monitor at 260 nm). Stripping and lyophilization gavethe mono-phenylcarbamate (48 mg, 27% yield), di-phenylcarbamate (16 mg,8%yield) and a trace amount of the triphenylcarbamate, as thetetraammonium salts. All three products were mixtures of thecorresponding 2′/3′ regiosiomers.

Mono-phenylcarbamate: ₁H NMR (D₂O, 300 MHz): δ 4.08-4.65 (m, 9H), 5.14(d, 1H), 5.75-5.94 (m, 4H), 7.01 (t, 1H), 7.22 (m, 4H), 7.76 (m, 2H).³¹P NMR (D₂O, 121.47 MHz): δ -10.17 (m, 2P), -21.81 (m, 2P).

Di-phenylcarbamate: ₁H NMR (D₂O, 300 MHz): δ 4.13-4.43 (m, 8H), 5.12 (m,2H), 5.84 (m, 4H), 7.01 (m, 2H), 7.21 (m, 8H), 7.75 (dd, 2H). ³¹P NMR(D₂O, 121.47 MHz): δ -10.19 (m, 2P), -21.65 (m, 2P).

Tri-phenylcarbamate: ¹H NMR (D₂O, 300 MHz): δ 4.29 (m, 7H), 4.5.10 (m,1H), 5.27 (m, 2H), 5.87 (m, 4H), 7.09 (m, 15H), 7.76 (d, 2H).). ³¹P NMR(D₂O, 121.47 MHz): δ -10.30 (m, 2P), -21.73 (m, 2P).

EXAMPLE 3 2′,3′-(benzyl)methylenedioxy-P¹,P⁴-Di(uridine5′-)tetraphosphate and P¹,P⁴-Di-(2′,3′-((benzyl)methylenedioxy) uridine5′-)tetraphosphate

P¹,P⁴-Di(uridine 5′-)tetraphosphate, tetrasodium salt (290 mg, 0.332mmol) was dissolved in 98% formic acid and phenylacetaldehyde, dimethylacetal (110 uL, 0.662 mmol) added. The reaction was stirred at ambienttemperature for 3 days, at which point TLC (silica gel, 50%isopropanol/50% ammonium hydroxide) and HPLC (C18) showed goodconversion to two less polar products. The formic acid was removed on arotary evaporator, and the residue partitioned between 0.7 M ammoniumbicarbonate (15 mL) and butyl acetate (15 mL). The layers were separatedand the aqueous was washed with a further portion of butyl acetate (10mL). The aqueous layer was stripped and the residue lyophilizedovernight. The crude product was dissolved in water (5 mL) and thecomponents separated by preparative HPLC (Waters Novapak C18, 6 um, 25 X100 mm, gradient from 0.1 M ammonium acetate to methanol over 30minutes, 30 mL/min, monitor at 260 nm). The yield of the monoacetal was88 mg (28%) and of the diacetal 60 mg (17%), both as the tetraammoniumsalts.

Monoacetal: ¹H NMR (D₂O, 300 MHz): δ 2.99 (d, 2H), 4.01-4.32 (m, 8H),4.77 (m, 2H), 5.33 (m, 2H), 5.74 (d, 1H), 5.81 (m, 2H), 7.21 (m, 5H),7.64 (d, 1H), 7.79 (d, 1H). ³¹P NMR (D₂O, 121.47 NHz): δ -10.18 (m, 1P),-10.78 (m, 1P), -22.00 (m, 2P).

Diacetal: ¹H NMR (D₂O, 300 MHz): δ 2.98 (d, 4H), 3.99 (m, 4H), 4.27 (m,2H), 5.27 (m, 2H), 5.36 (m, 2H), 5.73 (d, J=8.1 Hz, 2H), 7.21 (m, 10H),7.61 (d, J=8.1 Hz, 2H). ³¹P NMR (D₂O, 121.47 MHz): δ -10.57 (m, 2P),-21.81 (m, 2P).

EXAMPLE 4 3′-O-(phenylaminocarbonyl)-2′-deoxy (uridine 5′)-monophosphate

Deoxyuridine 5′-monophosphate, tetrabutylammonium salt (135 mg, 0.274mmol; prepared from the disodium salt by treatment with Dowex 50W×4 H⁺,following by stirring the resultant neutral species with excesstributylamine, stripping and lyophilization) was dissolved in dry DMF (1mL). Phenylisocyanate (60 uL, 0.547 mmol) was added and the mixtureheated overnight at 45° C., at which time TLC (silica gel, 50%isopropanol/50% ammonium hydroxide) and HPLC (C18) indicated asubstantial conversion to a less polar product. The DMF was stripped ona rotary evaporator and the oily residue partitioned between water (10mL) and ethyl acetate (10 mL). The layers were separated and the aqueouslayer was rewashed with ethyl acetate (2 X 10 mL). The water was removedand the residue was dissolved in water (2 mL). The product was isolatedby repeated injections onto semipreparative HPLC (AlltechNucleotide/Nucleoside C18, 7 um, 10 X 250 mm, gradient from 0.1 Mammonium acetate to methanol over 30 minutes, 5 mL/min, monitor at 260nm). The yield was 67 mg as the diammonium salt (53%).

¹H NMR (D₂O, 300 MHz): δ 2.21 (m, 2H), 3.84 (s, 2H), 4.13 (s, 1H), 5.08(d, 1H), 5.63 (d, 1H), 6.06 (t, 1H), 6.89 (br. t, 1H), 7.10 (m, 4H),7.72 (d, 1H). ³¹P NMR (D₂O, 121.47 MHz): δ -2.31 (s).

P¹-3′-O-(phenylaminocarbonyl)-2′-deoxyuridine 5′-)P⁴-(uridine5′-)tetraphosphate

Uridine 5′-triphosphate, ditributylammonium salt (prepared from thetrisodium salt by treatment with Dowex 50W×4 H⁺, followed by stirringthe resultant neutral species with excess tributylamine, stripping andlyophilization) is treated with 1.5 equivalents ofdicyclohexylcarbodiimide in DMF for 2 hours at room temperature. Thedicyclohexylurea is filtered off, and the resultant uridine 5′-cyclicaltriphosphate is treated with 3′-O-(phenylaminocarbonyl)-2′-deoxy(uridine 5′)-monophosphate, which is in the monotributylammonium saltform. The reaction mixture is stirred for several days at 45° C., andthe solvent is removed. The products are separated by preparative HPLC,as has been previously described.

EXAMPLE 5 2′(3′)-2-methylamino)benzoyl-P¹,P⁴-Di(uridine5′-)tetraphosphate and P¹,P⁴-Di-(2′(3′)-(2-methylamino)benzoyl uridine5′-)tetraphosphate

P¹,P⁴-Di(uridine 5′-) tetraphosphate, tetrasodium salt (800 mg, 0.93mmol) was dissolved in water (5 mL) and the pH adjusted to 7.6 by theaddition of solid sodium bicarbonate. N,N-dimethylformamide (DMF, 5 mL)was added, followed by N-methylisatoic anhydride (231 mg, 1.3 mmol) andthe suspension was heated at 50° C. for 2.5 hrs. TLC (silica gel, 50%isopropanol, 50% ammonium hydroxide) indicated that the reaction was notdone by this time, so a further portion of N-methylisatoic anhydride(100 mg, 0.56 mmol) was added and the reaction heated for another hour.The DMF was removed on a rotary evaporator and the residue was dissolvedin a minimum of water and applied to a DEAE Sephadex A-25 column (3 X 60cm). The column was eluted with a stepwise gradient from water to 1 Mammonium bicarbonate and the eluent monitored with a UV detector set at254 nm. The two products that eluted were collected separately and thesolvent was removed from each and the residue lyophilized overnight. ¹HNMR indicated that the first product to elute was the monoacylatedcompound, while the latter was the diacylated derivative, and that bothwere mixtures with the acylation at either the 2′ or 3′ hydroxyls, butwithout two carbamates on the same sugar. The yield of themonoaminobenzoylated product was 150 mg (16%); the yield of thediaminobenzoylated compound was 91 mg (8.7%).

Monoaminobenzoylated derivative: ¹H NMR (D₂O, 300 MHz): δ 2.70 (s, 3H),4.09-4.55(m, 9H), 5.34 (m, 1H), 5.71 (m, 2H), 5.83 (dd, 1H), 6.01 (m,1H), 6.57 (m, 1H), 6.65 (m, 1H), 7.25 (t, 1H), 7.72 (d, 2H), 7.81 (m,2H). ³¹P NMR (D₂O, 121.47 MHz): δ -10.20 (m, 2P), −21.83 (m,2P).

Diaminobenzoylated derivative: ¹H NMR (D₂O, 300 MHz): δ 2.69 (s, 6H),4.15-4.51 (m, 8H), 5.27 (m, 2H), 5.86 (m, 4H), 6.60 (m, 4H), 7.30 (m,2H), 7.79 (m, 4H). ³¹P NMR (D₂O, 121.47 MHz): δ -10.16 (m, 2P), -21.76(m, 2P).

EXAMPLE 6 P¹-(4-N-(4-methoxyphenyl)aminocarbonylcytidine5′-)-P⁴-(uridine 5′-) tetraphosphate

P¹-(cytidine 5′-)tetraphosphate, ditributylammonium salt (50 mg, 0.043mmol: prepared from the tetraammonium salt by treatment with Dowex 50W×4H⁺ in water, followed by mixing the protonated species with an excess oftributylamine in methanol, stripping and lyophilization) was dissolvedin dry DMF (1 mL) and tributylamine (10 uL, 0.43 mmol), andp-methoxyphenylisocyanate 8.4 uL, 0.648 mmol) were added in a singleportion. The homogeneous reaction mixture was heated overnight at 35°C., whereupon TLC (silica gel, 50% isopropanol/50% ammonium hydroxide)and HPLC (C18) indicated a substantial conversion to a single product.The solvent was removed on a rotary evaporator and the residue dissolvedin water (1 mL). The product was isolated by repeated injections onto asemi-preparative HPLC column (Alltech Nucleotide/Nucleoside C18, 7 um,10 X 250 mm, gradient from 0.1 M ammonium acetate to methanol over 30minutes, 5 mL/min, monitor at 260 nm). Stripping and lyophilization gavethe p-methoxyphenylurea (b 24 mg, 55% yield), as the tetraammonium salt.

The product so obtained can be derivatized on the 2′ and/or 3′ hydroxylgroups according to the foregoing methods (e.g. examples 2, 3,and 5).

¹H NMR (D₂O, 300 MHz): δ 3.59 (s, 3H), 4.01-4.20 (m, 10H), 5.68 (m, 3H),6.19 (d, 1H), 6.71 (d, 2H), 7.18 (d, 2H), 7.67 (d, 1H), 8.06 (d, 1H).³¹P NMR (D₂O, 121. 47 MHz): δ -10.13 (m, 2P), -21.76 (m, 2P).

EXAMPLE 7 P¹-((4-bromophenyl)ethenocytidine 5′-)-P⁴-(uridine 5′-)tetraphosphate

P¹-(cytidine 5′-)-P⁴-(uridine 5′-) tetraphosphate, tetrasodium salt (500mg, 0.57 mmol) was dissolved in water (5 mL) and a solution of 2,4′-dibromoacetophenone (792 mg, 2.85 mmol) in DMF (15 mL) added. Themixture was heated overnight at 40° C., and a further portion of thedibromoketone (400 mg, 1.44 mmol) in DMF (5 mL) added. The rection washeated a further 5 hrs, and the solvents removed by evaporation. Theresidue was partitioned between water (20 mL) and ethyl acetate (25 mL)and the layers separated. The aqueous layer was washed with furtherethyl acetate (2×15 mL) and the aqueous evaporated to dryness. Theresidue was dissolved in water (5 mL) and the product was isolated byrepeated injections onto a semi-preparative HPLC column (see example 6for conditions). The yield of the pure etheno compound was 80 mg (13.5%)

¹H NMR (D₂O, 300 MHz): δ 4.06 (m, 8H), 4.36 (m, 2H), 5.64 (dd, 2H), 6.07(d, 1H), 6.74 (d, 1H), 7.45 (d, 2H), 7.54 (d, 2H), 7.59 (d, 1H), 7.63(d, 1H), 7.93 (s, 1H). ³¹P NMR (D₂O, 121.47 MHz): δ -10.09 (m, 2P),-21.59 (m, 2P).

EXAMPLE 8 P¹-((4-bromophenyl)etheno-2′-deoxycytidine 5′-)-P⁴-(uridine5′-) tetraphosphate

Example 8 product was prepared from 100 mg P¹-(2′-deoxycytidine5′-)-P⁴-(uridine 5′-) tetraphosphate, tetrasodium salt and2,4′-dibromoacetophenone, according to the general method of example 7.Yield=35 mg (30%).

¹H NMR (D₂O, 300 MHz): δ 2.31 (m, 2H), 4.03 (m, 8H), 5.60 (dd, 2H), 6.41(t, 1H), 6.73 (d, 1H), 7.53 (m, 5H), 7.65 (d, 1H), 7.93 (s, 1H). ³¹P NMR(D₂O, 121.47 MHz): δ -10.11 (m, 2P), -21.58 (m, 2P).

EXAMPLE 9 P¹, P⁴-Di((4-bromophenyl)ethenocytidine 5′-)-tetraphosphate

Example 9 product was prepared from 50 mg P¹,P4-Di(cytidine 5′-)tetraphosphate, tetrasodium salt and 2,4′-dibromoacetophenone, accordingto the general method of example 7. Yield=20 mg (29%).

¹H NMR (D₂O, 300 MHz): δ 4.24 (m, 10H), 5.98 (d, 2H), 6.39 (d, 2H), 7.14(m, 8H), 7.45 (m, 4H).). ³¹P NMR (D₂O, 121.47 MHz): β -10.13 (m, 2P),-21.68 (m, 2P).

EXAMPLE 10 P¹-((4-phenylphenyl)ethenocytidine 5′-)-P⁴-(cytidine 5′-)tetraphosphate

Example 10 was product prepared from 50 mg P¹,P4-Di(cytidine 5′-)tetraphosphate, tetrasodium salt and 2-bromo-4′-phenylacetophenone,according to the general method of example 7. Yield=15 mg (13%). ¹H NMR(D₂O, 300 MHz): β 4.10 (m, 10H), 5.48 (d, 1H), 5.87 (m, 2H), 6.68 (d,1H), 7.20 (m, 3H), 7.36 (m, 6H), 7.68 (m, 3H). ³¹P NMR (D₂O, 121.47MHz): δ -10.08 (m, 2P), -21.78 (m, 2P).

The products of examples 7-10 can be further derivatized according tothe methods of examples 2, 3, and 5, to give bifunctional molecules thatfall within the scope of the invention.

Those skilled in the art will recognize various synthetic methodologieswhich may be employed to prepare non-toxic pharmaceutically acceptablesalts and acylated prodrugs of the compounds.

The active compounds may be administered systemically to target sites ina subject in need such that the extracellular concentration of a P2Y_(τ)antagonist is elevated to block the binding of ADP to P2Y_(τ) receptors,thus inhibit the platelet aggregation. The term systemic as used hereinincludes subcutaneous injection, intravenous, intramuscular,intrasternal injection, intravitreal injection, infusion, inhalation,transdermal administration, oral administration, rectal administrationand intra-operative instillation.

For systemic administration such as injection and infusion, thepharmaceutical formulation is prepared in a sterile medium. The activeingredient, depending on the vehicle and concentration used, can eitherbe suspended or dissolved in the vehicle. Adjuvants such as localanesthetics, preservatives and buffering agents can also be dissolved inthe vehicle. The sterile indictable preparation may be a sterileindictable solution or suspension in a non-toxic acceptable diluent orsolvent. Among the acceptable vehicles and solvents that may be employedare sterile water, saline solution, or Ringer's solution.

Another method of systemic administration of the active compoundinvolves oral administration, in which pharmaceutical compositionscontaining active compounds are in the form of tablets, lozenges,aqueous or oily suspensions, viscous gels, chewable gums, dispersiblepowders or granules, emulsion, hard or soft capsules, or syrups orelixirs.

For oral use, an aqueous suspension is prepared by addition of water todispersible powders and granules with a dispersing or wetting agent,suspending agent one or more preservatives, and other excipients.Suspending agents include, for example, sodium carboxymethylcellulose,methylcellulose and sodium alginate. Dispersing or wetting agentsinclude naturally-occurring phosphatides, condensation products of anallylene oxide with fatty acids, condensation products of ethylene oxidewith long chain aliphatic alcohols, condensation products of ethyleneoxide with partial esters from fatty acids and a hexitol, andcondensation products of ethylene oxide with partial esters derived fromfatty acids and hexitol anydrides. Preservatives include, for example,ethyl, and n-propyl p-hydroxybenzoate. Other excipients includesweetening agents (e.g., sucrose, saccharin), flavoring agents andcoloring agents. Those skilled in the art will recognize the manyspecific excipients and wetting agents encompassed by the generaldescription above.

For oral application, tablets are prepared by mixing the active compoundwith nontoxic pharmaceutically acceptable excipients suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. Formulations fororal use may also be presented as hard gelatin capsules wherein theactive ingredient is mixed with an inert solid diluent, for example,calcium carbonate, calcium phosphate or kaolin, or as soft gelatincapsules wherein the active ingredient is mixed with water or an oilmedium, for example, peanut oil, liquid paraffin or olive oil.Formulation for oral use may also be presented as chewable gums byembedding the active ingredient in gums so that the active ingredient isslowly released upon chewing.

Additional means of systemic administration of the active compound tothe target platelets of the subject would involve a suppository form ofthe active compound, such that a therapeutically effective amount of thecompound reaches the target sites via systemic absorption andcirculation.

For rectal administration, the compositions in the form of suppositoriescan be prepared by mixing the active ingredient with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the compound. Such excipients include cocoa butter andpolyethylene glycols.

The active compounds may also be systemically administered to theplatelet aggregation sites through absorption by the skin usingtransdermal patches or pads. The active compounds are absorbed into thebloodstream through the skin. Plasma concentration of the activecompounds can be controlled by using patches containing differentconcentrations of active compounds.

One systemic method involves an aerosol suspension of respirableparticles comprising the active compound, which the subject inhales. Theactive compound would be absorbed into the bloodstream via the lungs,and subsequently contact the target platelets in a pharmaceuticallyeffective amount. The respirable particles may be liquid or solid, witha particle size sufficiently small to pass through the mouth and larynxupon inhalation; in general, particles ranging from about 1 to 10microns, but more preferably 1-5 microns, in size are consideredrespirable.

Another method of systemically administering the active compounds to theplatelet aggregation sites of the subject involves administering aliquid/liquid suspension in the form of eye drops or eye wash or nasaldrops of a liquid formulation, or a nasal spray of respirable particlesthat the subject inhales. Liquid pharmaceutical compositions of theactive compound for producing a nasal spray or nasal or eye drops may beprepared by combining the active compound with a suitable vehicle, suchas sterile pyrogen free water or sterile saline by techniques known tothose skilled in the art.

Intravitreal delivery may include single or multiple intravitrealinjections, or via an implantable intravitreal device that releasesP2Y_(τ) antagonists in a sustained capacity. Intravitreal delivery mayalso include delivery during surgical manipulations as either an adjunctto the intraocular irrigation solution or applied directly to thevitreous during the surgical procedure.

For systemic administration, plasma concentrations of active compoundsdelivered may vary according to compounds; but are generally1×10⁻¹⁰−1×10⁻⁵ moles/liter, and preferably 1×10⁻⁸−1×10⁻⁶ moles/liter.

The pharmaceutical utility of P2Y agonist compounds of this inventionare indicated by the inositol phosphate assay for P2Y activity. Thiswidely used assay, as described in E. Lazarowski, et al., Brit. J.Pharm. 116, 1619-27 (1995), relies on the measurement of inositolphosphate formation as a measurement of activity of compounds activatingreceptors linked via G-proteins to phospholipase C.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them.

EXAMPLE 11 Inhibition of ADP-Induced Platelet Aggregation

Isolation of Platelets: Human blood was obtained from informed healthyvolunteers. Blood was collected into one-sixth volume of ACD (2.5 g ofsodium citrate, 1.5 g citric acid, and 2.5 g glucose in 100 ml dH₂O).Blood was centrifuged at 800×g for 15 min at room temperature and theplatelet-rich plasma removed and incubated for 60 min at 37° C. in thepresence of 1 mM acetylsalicylic acid followed by centrifugation at1000×g for 10 min at room temperature. The platelet pellet wasresuspended at a density of 2×10⁸ cells/ml with HEPES-buffered Tyrode'ssolution (137 mM NaCl, 2.7 mM KCl, 1 mM MgCl₂, 3 mM NaH₂PO₄, 5 mMglucose, 10 mM HEPES pH 7.4, 0.2% bovine serum albumin, and 0.05 U/mlapyrase).

Aggregation Studies: ADP-induced platelet aggregation was determined bymeasuring the transmission of light through a 0.5 ml suspension ofstirred (900 rpm) aspirin-treated washed platelets in alumi-aggregometer at 37° C. (Chrono-Log Corp. Havertown, Pa.). Thebaseline of the instrument was set using 0.5 ml of Hepes-bufferedTyrode's solution. Prior to aggregation measurements, the plateletsuspension was supplemented with 2 mM CaCl₂ and 1 mg/ml fibrinogen.Platelet aggregation was initiated by the addition of indicatedconcentrations of ADP or other agonists, and the light transmissioncontinuously recorded for at least 8 min. When inhibitors of plateletaggregation were tested, platelets were incubated for 3-6 min in thepresence of indicated concentrations of inhibitor before addition of ADPor other agonists, and the response recorded for at least 8 min. Thepotency of agonists and inhibitors of platelet aggregation wereestimated from both, the rate of aggregation and the maximal extent ofaggregation obtained for each determination by fitting the data to afour parameter logistic equation (Graph-Pad Corp).

EXAMPLE 12 Effects on Platelet Aggregation In Vivo

To evaluate the ability of these compounds to inhibit plateletaggregation in vivo, an experimental protocol similar to the method ofR. G. Humphries et al. (Br. J. Pharmacol. 115:1110-1116, 1995) will beperformed.

Surgical Preparation and Instrumentation: Male Sprague-Dawley rats areanesthetized. Body temperature is maintained at 37±0.5° C. with aheating lamp. Animals breathe spontaneously and a tracheotomy isperformed to ensure a patent airway. A cannula containing heparinizedsaline is introduced into the left femoral artery and connected to atransducer to record blood pressure and heart rate. Cannulae containingnon-heparinized saline are introduced into the left common carotidartery and left jugular vein for withdrawal of arterial blood samplesand i.v. administration of compounds.

Experimental Protocol: Either compound or vehicle is administered toeach animal as an infusion. Blood samples are taken immediately prior tothe first infusion, at the end of each infusion and 20 min aftercessation of the final infusion for measurement of platelet aggregationex vivo. Immediately after sampling, ADP-induced platelet aggregation ismeasured in duplicate in 0.5 ml blood samples diluted 1:1 with salineand incubated at 37° C. for 4 min. For the final minute of this period,cuvettes are transferred to a lumi-aggregometer and the sample stirredat 900 rpm. ADP (3M) is added in a volume of 20 1 and the aggregationresponse is recorded.

EXAMPLE 13 Inhibition of Thrombus Formation in Anesthetized Rats

To evaluate the effect of these compounds on thrombus formation in vivo,the following experimental protocol will be performed.

Rats (CD-1; male; approximately 350 grams; Charles River, Raleigh,N.C.), are anesthetized with sodium pentobarbital (70 mg/kg i.p.). Theabdomens are shaved and a 22 gauge intravenous catheter is inserted intoa lateral tail vein. A midline incision is made and the intestines arewrapped in saline-soaked gauze and positioned so the abdominal aorta isaccessible. The inferior vena cava and abdominal aorta are carefullyisolated and a section (approx. 1 cm) of the abdominal aorta (distal tothe renal arteries proximal to the bifurcation) is dissected. Allbranches from the aorta in this section are ligated with 4-0 silksuture. A 2.5 mm diameter flow probe connected to a Transonic flow meteris placed on the artery and a baseline (pre-stenosis) flow is recorded.Two clips are placed around the artery decreasing the vessel diameter byapproximately 80%. A second baseline flow measurement is taken(post-stenosis) and the hyperemic response is tested. Animals are thentreated with either compound or saline i.v., via tail vein catheter.Thrombosis is induced five minutes after treatment by repeated externalcompressions of the vessel with hemostatic forceps. Two minutespost-injury, the vessel compressions are repeated and a 10 minute periodof flow monitoring is started. Animals are monitored continuously for aminimum of the first ten minutes post-injury. After twenty minutes(post-injury), a flow measurement is repeated and the animals areeuthanized. The section of the aorta that includes the injured sectionis harvested and placed in 10% formalin for possible histologicevaluation.

EXAMPLE 14 Inhibition of Thrombus Formation in Anesthetized Dogs

To evaluate the effect of these compounds on dynamic thrombus formationin vivo, the following experimental protocol similar to the method of J.L. Romson et al. (Thromb. Res. 17:841-853, 1980) will be performed.

Surgical Preparation and Instrumention: Briefly, purpose-bred dogs areanesthetized, intubated and ventilated with room air. The heart isexposed by a left thoracotomy in the fifth intercostal space andsuspended in a pericardial cradle. A 2-3 cm segment of the leftcircumflex coronary artery (LCCA) is isolated by blunt dissection. Theartery is instrumented from proximal to distal with a flow probe, astimulation electrode, and a Goldblatt clamp. The flow probe monitorsthe mean and phasic LCCA blood flow velocities. The stimulationelectrode and its placement in the LCCA and the methodology to induce anocclusive coronary thrombus have been described previously (J. K.Mickelson et al., Circulation 81:617-627, 1990; R. J. Shebuski et al.,Circulation 82:169-177, 1990; J. F. Tschopp et al., Coron. Artery Dis.4:809-817, 1993).

Experimental Protocol: Dogs are randomized to one of four treatmentprotocols (n=6 per treatment group) in which the control group receivessaline i.v. and the three drug-treated groups are administered compoundi.v. Upon stabilization from the surgical interventions, dogs receiveeither saline or compound. After approximately 30 minutes, an anodalcurrent is applied to the LCCA for 180 min. The number and frequency ofcyclic flow variations (CFV) that precede formation of an occlusivethrombus are recorded. These cyclic phenomena are caused by plateletthrombi that form in the narrowed lumen as a result of plateletaggregation (J. D. Folts et al., Circulation 54:365-370, 1976; Bush etal., Circulation 69:1161-1170, 1984). Zero flow in the LCCA for aminimum of 30 minutes indicates a lack of antithrombotic efficacy (L.G.Frederick et al., Circulation 93:129-134, 1996).

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be obvious that certain changes and modificationsmay be practiced within the scope of the appended claims.

All publications, patents, and patent applications are hereinincorporated by reference in their entirety to the same extent as ifindividual publication, patent, or patent application was specificallyand individually indicated to be incorporated by reference in itsentirety.

1. A pharmaceutical formulation comprising a compound of general formulaI, or salts thereof:

wherein: X₁, X₂, and X₃ are independently selected from the groupconsisting of oxygen, methylene, monochloromethylene, dichloromethylene,monofluoromethylene, difluoromethylene, and imido; T, W, and V areindependently oxygen or sulfur; m=0, 1 or 2; n=0, 1, or 2; p=0, 1, or 2;M=H or a pharmaceutically-acceptable inorganic or organic counterion;D₁=O or C; B′ is a purine or a pyrimidine residue according to generalformulas IV and V which is linked to the 1′ position of the furanose orcarbocycle via the 9- or 1-position, respectively; A is M or alkyl; or Ais a nucleoside residue which is defined as:

and which is linked to the phosphate chain via the 5′ position of thefuranose or carbocycle; wherein: D₂=O or C; B is a purine or apyrimidine residue according to general formulas IV and V which islinked to the sugar or carbocycle via the 9- or 1-position,respectively; wherein when D₁ and D₂ are oxygen, the furanose is in theβ-configuration; Y′=H, OH, or OR₁, where OR₁ falls under the definitionof general Formula II or III; Z′=OH or OR₂, where OR₂ falls under thedefinition of general Formula II or III; Z=OH or OR₃, where OR₃ fallsunder the definition of general formula II or III; Y=H, OH, or OR₄,where OR₄ falls under the definition of general Formula II or III;provided that at least one of Y′, Z′, Z, and Y is OR₁, OR₂, OR₃, or OR₄,respectively; wherein compounds of general Formula I are molecules whosestructures fall within the definitions of Formula Ia and Formula Ib:

X₁, X₂, and X₃=O; T, V, and W=O; M=H, NH₄ ⁺, Na⁺ or otherpharmaceutically-acceptable inorganic or organic counterion; Y′=H, OH,or OR₁, where OR₁ falls under the definition of general formula II;Z′=OH or OR₂, where OR₂ falls under the definition of general formulaII; Z=OH or OR₃, where OR₃ falls under the definition of general formulaII; Y=H, OH, or OR₄, where OR₄ falls under the definition of generalformula II; provided that at least one of Y′, Z′, Z, and Y is OR₁, OR₂,OR₃, or OR₄, respectively; D₁=O; D₂=O or C; B and B′ are purine orpyrimidine residues according to general formulas IV and V; m and p=0, 1or 2; n=0 or 1; such that the sum of m+n+p is from 0 to 5; or X₁, X₂,and X₃=O; T, V, and W=O; M=H, NH₄ ⁺, Na⁺ or otherpharmaceutically-acceptable inorganic or organic counterion; Y′=H, OH,or OR₁, where OR₁ falls under the definition of general formula III;Z′=OH or OR₂, where OR₂ falls under the definition of general formulaIII; Z=OH or OR₃, where OR₃ falls under the definition of generalformula III; Y=H, OH, or OR₄, where OR₄ falls under the definition ofgeneral formula III; provided that at least one of Y′, Z′, Z, and Y isOR₁, OR₂, OR₃, or OR₄, respectively; D₁=O; D₂=O or C; B and B′ arepurine or pyrimidine residues according to general formulas IV and V; mand p=0, 1 or 2; n=0 or 1; such that the sum of m+n+p is from 0 to 5; orX₁ and X₃=O; X₂ is selected from the group consisting of methylene,monochloromethylene, dichloromethylene, monofluoromethylene,difluoromethylene, and imido; T, V, and W=O; M=H, NH₄ ⁺, Na⁺ or otherpharmaceutically-acceptable inorganic or organic counterion; Y′=H, OH,or OR₁, where OR₁ falls under the definition of general formula II;Z′=OH or OR₂, where OR₂ falls under the definition of general formulaII; Z=OH or OR₃, where OR₃ falls under the definition of general formulaII; Y=H, OH, or OR₄, where OR₄ falls under the definition of generalformula II; provided that at least one of Y′, Z′, Z, and Y is OR₁, OR₂,OR₃, or OR₄, respectively; D₁=O; D₂=O or C; B and B′ are purine orpyrimidine residues according to general formulas IV and V; m and p=0, 1or 2; n=1; such that the sum of m+n+p is from 0 to 5; or X₁ and X₃=O; X₂is selected from the group consisting of methylene, monochloromethylene,dichloromethylene, monofluoromethylene, difluoromethylene, and imido; T,V, and W=O; M=H, NH₄ ⁺, Na⁺ or other pharmaceutically-acceptableinorganic or organic counterion; Y′=H, OH, or OR₁, where OR₁ falls underthe definition of general formula III; Z′=OH or OR₂, where OR₂ fallsunder the definition of general formula III; Z=OH or OR₃, where OR₃falls under the definition of general formula III; Y=H, OH, or OR₄,where OR₄ falls under the definition of general formula III; providedthat at least one of Y′, Z′, Z, and Y is OR₁, OR₂, OR₃, or OR₄,respectively; D₁=O; D₂ is O or C; B and B′ are purine or pyrimidineresidues according to general formulas IV and V; m and p=0, 1 or 2; n=1;such that the sum of m+n+p is from 0 to 5; or X₁ and X₃=O; X₂ isselected from the group consisting of methylene, monochloromethylene,dichloromethylene, monofluoromethylene, difluoromethylene, and imido;T=S; V and W=O; M=H, NH₄ ⁺, Na⁺ or other pharmaceutically-acceptableinorganic or organic counterion; Y′=H, OH, or OR₁, where OR₁ falls underthe definition of general formula II; Z′=OH or OR₂, where OR₂ fallsunder the definition of general formula II; Z=OH or OR₃, where OR₃ fallsunder the definition of general formula II; Y=H, OH, or OR₄, where OR₄falls under the definition of general formula II; provided that at leastone of Y′, Z′, Z, and Y is OR₁, OR₂, OR₃, or OR₄, respectively; D₁=O;D₂=O or C; B and B′ are purine or pyrimidine residues according togeneral formulas IV and V; m, n and p=1; or X₁ and X₃=O; X₂ is selectedfrom the group consisting of methylene, monochloromethylene,dichloromethylene, monofluoromethylene, difluoromethylene, and imido;T=S; V and W=O; M is selected from the group consisting of H, NH₄ ⁺, Na⁺and other pharmaceutically-acceptable inorganic or organic counterion;Y′=H, OH, or OR₁, where OR₁ falls under the definition of generalformula III; Z′=OH or OR₂, where OR₂ falls under the definition ofgeneral formula III; Z=OH or OR₃, where OR₃ falls under the definitionof general formula III; Y=H, OH, or OR₄, where OR₄ falls under thedefinition of general formula III; provided that at least one of Y′, Z′,Z, and Y is OR1, OR2, OR3, or OR4, respectively; D₁=O; D₂=O or C; B andB′ are purine or pyrimidine residues according to general formulas IVand V; m, n, and p=1;

wherein: A is M or alkyl; X₁ and X₂=O; T, V, and W=O; M=H, NH₄ ⁺, Na orother pharmaceutically-acceptable inorganic or organic counterion; Y′=H,OH, or OR₁, where OR₁ falls under the definition of general formula II;Z′=H, OH or OR₂, where OR₂ falls under the definition of general formulaII; with the provision that at least one of Y′ and Z′ is OR₁ or OR₂;D₁=O or C; B′ is purine or pyrimidine residue according to generalformulas IV and V; n and p are 0, 1, or 2 such that the sum of n+p isfrom 1 to 3; or A is M or alkyl; X₁ and X₂=O; T, V, and W=O; M isselected from the group consisting of H, NH₄ ⁺, Na⁺ and otherpharmaceutically-acceptable inorganic or organic counterion; Y′=OR₁,where OR₁ falls under the definition of general formula III; Z′=OR₂,where OR₂ falls under the definition of general formula III; D₁=O or C;B′ is purine or pyrimidine residue according to general formulas IV andV; n and p are 0, 1, or 2 such that the sum of n+p is from 1 to 3; or Ais M or alkyl; X₁ and X₂=O; T and V=O; W=S; M=H, NH₄ ⁺, Na⁺ or otherpharmaceutically-acceptable inorganic or organic counterion; Y′=H, OH,or OR₁, where OR₁ falls under the definition of general formula II;Z′=H, OH or OR₂, where OR₂ falls under the definition of general formulaII; with the provision that at least one of Y′ and Z′ is OR₁ or OR₂;D₁=O or C; B′ is purine or pyrimidine residue according to generalformulas IV and V; p is 0, 1, or 2 such that the sum of n+p is from 1 to3; n=1; or A is M or alkyl; X₁ and X₂=O; T and V=O; W=S; M is selectedfrom the group consisting of H, NH₄ ⁺, Na⁺ and otherpharmaceutically-acceptable inorganic or organic counterion; Y′=OR₁,where OR₁ falls under the definition of general formula III; Z′=OR₂,where OR₂ falls under the definition of general formula III; D₁=O or C;B′ is purine or pyrimidine residue according to general formulas IV andV; p is 0, 1, or 2 such that the sum of n+p is from 1 to 3; n=1; or A isM or alkyl; X₁=O; X₂ is selected from the group consisting of methylene,monochloromethylene, dichloromethylene, monofluoromethylene,difluoromethylene, and imido; T, V, and W=O; M is selected from thegroup consisting of H, NH₄ ⁺, Na⁺ and other pharmaceutically-acceptableinorganic or organic counterion; Y′=H, OH, or OR₁, where OR₁ falls underthe definition of general formula II; Z′=H, OH or OR₂, where OR₂ fallsunder the definition of general formula II; with the provision that atleast one of Y′ and Z′ is OR₁ or OR₂; D₁=O or C; B′ is purine orpyrimidine residue according to general formulas IV and V; p is 0, 1, or2 such that the sum of n+p is from 1 to 3; n=1; or A is M or alkyl;X₁=O; X₂ is selected from the group consisting of methylene,monochloromethylene, dichloromethylene, monofluoromethylene,difluoromethylene, and imido; T, V, and W=O; M is selected from thegroup consisting of H, NH₄ ⁺, Na⁺ and other pharmaceutically-acceptableinorganic or organic counterion; Y′=H, OH, or OR₁, where OR₁ falls underthe definition of general formula III; Z′=H, OH or OR₂, where OR₂ fallsunder the definition of general formula III; D₁=O or C; B′ is purine orpyrimidine residue according to general formulas IV and V; p is 0, 1, or2 such that the sum of n+p is from 1 to 3; n=1; wherein, for compoundsaccording to Formula Ia or Ib, where Y′=OR₁, Z′=OR₂, Z=OR₃ and/or Y=OR₄,at least one of the four is a residue which is linked directly to thecorresponding 2′ or 3′ hydroxyl oxygen of the furanose or carbocycle viaa carbon atom; wherein said residue falls within the scope of formula IIor formula III:

wherein: O is the corresponding 2′ or 3′ oxygen of the furanose orcarbocycle; R₅, R₆, and R₇ are selected from the group consisting of H,an alkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl, andsubstituted aryl, such that the moiety defined according to formula IIis an ether; or R₅ and R₆ are taken together to be oxygen or sulfurdoubly bonded to Q, and R₇ is selected from the group consisting ofalkyl, cycloalkyl, aralkyl, and substituted aralkyl, such that themoiety defined according to formula II is an ester or thioester; or R₅and R₆ are taken together to be oxygen or sulfur doubly bonded to Q, andR₇ is amino or mono- or disubstituted amino, where the substituents areselected from the group consisting of alkyl, cycloalkyl, aralkyl, aryl,substituted aralkyl, and substituted aryl, such that the moietyaccording to formula II is a carbamate or thiocarbamate; or R₅ and R₆are taken together to be oxygen or sulfur doubly bonded to Q, and R₇ isselected from the group consisting of alkoxy, cycloalkoxy, aralkyloxy,aryloxy, substituted aralkyloxy, and substituted aryloxy, such that themoiety according to formula II is a carbonate or thiocarbonate; or R₅and R₆ are taken together to be oxygen or sulfur doubly bonded to Q andboth the 2′ and 3′ oxygens of the furanose are directly bound to Q toform a cyclical carbonate or thiocarbonate, R₇ is not present;

wherein: O is the 2′ and 3′ oxygens of the furanose or carbocycle; andthe 2′ and 3′ oxygens of the furanose or carbocycle are linked by acommon carbon atom to form a cyclical acetal, cyclical ketal, orcyclical orthoester; and for cyclical acetals and ketals, R₈ and R₉ areindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aralkyl, aryl, substituted aralkyl, and substituted aryl; orare joined together to form a homocyclic or heterocyclic ring composedof 3 to 8 atoms, or for cyclical orthoesters, R₈ is selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, aralkyl, aryl,substituted aralkyl, and substituted aryl, and R₉ is selected from thegroup consisting of alkyloxy, cycloalkyloxy, aralkyloxy, aryloxy,substituted aralkyloxy, and substituted aryloxy; B and B′ areindependently a purine residue, as in formula IV, linked through the9-position, or a pyrimidine residue, as in formula V, linked through the1-position; wherein, provided when D₁ and D₂ are oxygen, the ribosylmoieties are in the D-configuration;

wherein: R₁₀ and R₁₄ are selected from the group consisting of hydroxy,oxo, amino mercapto, alkylthio, alkyloxy, aryloxy, alkylamino,cycloalkylamino, aralkylamino, arylamino, diaralkylamino, diarylamino,and dialkylamino, where the alkyl groups are optionally linked to form aheterocycle; or R₁₀ and R₁₄ are acylamino according to Formula VI,provided that they incorporate an amino residue from the C-6 position ofthe purine or the C-4 position of the pyrimidine; or when R₁₀ in apurine or R₁₄ in a pyrimidine has as its first atom nitrogen, R₁₀ andR₁₁ or R₁₄ and R₁₅ are taken together to form a 5-membered fusedimidazole ring, optionally substituted on the etheno ring with R₅-R₉selected from the group consisting of alkyl, cycloalkyl, aralkyl, oraryl moieties, as described above; J is carbon or nitrogen, with theprovision that when nitrogen, R₁₂ is not present; R₁₁ is hydrogen, O oris absent; R₁₂ is selected from the group consisting of hydrogen, alkyl,azido, alkylamino, arylamino, aralkylamino, alkoxy, aryloxy, aralkyloxy,alkylthio, arythio, aralkylthio, and ω-A(C₁₋₆alkyl)B- wherein A and Bare selected from the group consisting of independently amino, mercapto,hydroxy and carboxyl; R₁₃ is selected from the group consisting ofhydrogen, chlorine, amino, monosubstituted amino, disubstituted amino,alkylthio, arylthio, and aralkylthio, where the substituent on sulfurcontains up to a maximum of 20 carbon atoms, with or withoutunsaturation; R₁₅ is selected from the group consisting of hydrogen, andacyl, such as acetyl, benzoyl, phenylacyl, with or without substituents;R₁₆ is selected from the group consisting of hydrogen, methyl, alkyl,halo, alkyl, alkenyl, substituted alkenyl, alkynyl, and substitutedalkynyl;

wherein: NH is the amino residue at the C-6 position in a purine or theamino residue at the C-4 position in a pyrimidine; Q is a carbon atom; Wis oxygen or sulfur; R₁₇ is amino or mono- or disubstituted amino suchthat the moiety according to formula VI is a urea or thiourea; or R₁₇ isselected from the group consisting of alkoxy, aralkyloxy, aryloxy,substituted aralkyloxy, and substituted aryloxy, such that the moietyaccording to formula VI is a carbamate or thiocarbamate; or R₁₇ isselected from the group consisting of alkyl, cycloalkyl, aralkyl, andaryl, with or without substituents or heteroatoms, such that the moietyaccording to formula VI is an amide.
 2. The compound according to claim1, wherein said compound is fluorescently labeled and used as abiochemical probe for the P2_(T) receptor.
 3. A method of treatingdiseases or conditions associated with platelet aggregation comprising:administering to a patient a pharmaceutical formulation according toclaim 1, wherein said compound is effective to bind the P2_(T) receptorson platelets and inhibit ADP-induced platelet aggregation.
 4. The methodaccording to claim 3, wherein said pharmaceutical formulation isadministered to reduce the incidence of dose-related adverse sideeffects of other therapeutic agents used to prevent, manage or treatplatelet aggregation disorders.
 5. The method according to claim 3,wherein said administering is systemic administration of said compound.6. The method according to claim 5, wherein said systemic administrationis administration of an injectable form of said compound, such that atherapeutically effective amount of said compound contacts the targetplatelets of said patient via systemic absorption and circulation. 7.The method according to claim 5, wherein said systemic administration isaccomplished by administering an oral form of said compound, such that atherapeutically effective amount of said compound contacts the targetplatelets of said patient via systemic absorption and circulation. 8.The method according to claim 5, wherein said systemic administration isadministration of said compound in a form of a transdermal patch or atransdermal pad, such that a therapeutically effective amount of saidcompound contacts the target platelets of said patient via systemicabsorption and circulation.
 9. The method according to claim 5, whereinsaid systemic administration is administration of a liquid/liquidsuspension of said compound via nose drops or nasal spray, oradministration of a nebulized liquid to oral or nasopharyngeal airwaysof said subject, such that a therapeutically effective amount of saidcompound inhibits platelet aggregation.
 10. The method according toclaim 5, wherein said systemic administration comprises infusion of saidcompound to target platelets via a device selected from a groupconsisting of a pump catheter system and a continuous or selectiverelease device.
 11. The method according to claim 5, wherein saidsystemic administration is administration of a suppository form of saidcompound, such that a therapeutically effective amount of said compoundcontacts the target platelets of said patient via systemic absorptionand circulation.
 12. The method according to claim 5, wherein saidsystemic administration is vaginal administration in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles.
 13. The method according toclaim 5, wherein said compound is administered to a patient by anintravitreal delivery.
 14. The method according to claim 5, wherein saidsystemic administration is administration of an intra-operativeinstillation of a gel, cream, powder, foam, crystals, liposomes, sprayor liquid suspension form of said compound, such that a therapeuticallyeffective amount of said compound contracts the target platelets of saidpatient via systemic absorption and circulation.
 15. The methodaccording to claim 3, wherein said diseases or conditions associatedwith platelet aggregation are disorders or procedures characterized bythrombosis, primary arterial thrombotic complications of atheroscleroticdisease, thrombotic complications of interventions of atheroscleroticdisease, thrombotic complications of surgical or mechanical damage,mechanically-induced platelet activation, shunt occlusion, thrombosissecondary to vascular damage and inflammation, indications with adiffuse thrombotic/platelet consumption component, venous thrombosis,coronary arterial thrombosis, pathological effects of atherosclerosisand arteriosclerosis, platelet aggregation and clot formation in bloodand blood products during storage, chronic or acute states ofhyper-aggregability, reocclusion of an artery or vein followingfibrinolytic therapy, platelet adhesion associated with extracorporealcirculation, thrombotic complications associated with thrombolytictherapy, thrombotic complications associated with coronary and otherangioplasty, or thrombotic complications associated with coronary arterybypass procedures.
 16. The method according to claim 15, wherein saiddisorders or procedures characterized with thrombosis are unstableangina, coronary angioplasty, or myocardial infarction.
 17. The methodaccording to claim 15, wherein said primary arterial thromboticcomplications of atherosclerosis are thrombotic stroke, peripheralvascular disease, or myocardial infarction without thrombolysis.
 18. Themethod according to claim 15, wherein said thrombotic complications ofinterventions of atherosclerotic disease are associated withangioplasty, endarterectomy, stent placement, coronary or other vasculargraft surgery.
 19. The method according to claim 15, wherein saidthrombotic complications of surgical or mechanical damage are associatedwith tissue salvage following surgical or accidental trauma,reconstructive surgery including skin flaps, or reductive surgery suchas breast reduction.
 20. The method according to claim 15, wherein saidmechanically-induced platelet activation is caused by cardiopulmonarybypass resulting in microthromboembolism.
 21. The method according toclaim 15, wherein said shunt occlusion is renal dialysis orplasmapheresis.
 22. The method according to claim 15, wherein saidthrombosis secondary to vascular damage and inflammation is vasculitis,arteritis, glomerulonephritis or organ graft rejection.
 23. The methodaccording to claim 15, wherein said indications with a diffusethrombotic/platelet consumption component are disseminated intravascularcoagulation, thrombotic thrombocytopenic purpura, hemolytic uremicsyndrome, heparin-induced thrombocytopenia, or pre-eclampsia/eclampsia.24. The method according to claim 15, wherein said venous thrombosis isdeep vein thrombosis, veno-occlusive disease, hematological conditions,or migraine.
 25. The method according to claim 24, wherein saidhematological conditions are thrombocythemia or polycythemia.
 26. Themethod according to claim 15, wherein said coronary arterial thrombosisis associated with unstable angina, coronary angioplasty or acutemyocardial infarction.
 27. The method according to claim 15, whereinpathological effects of atherosclerosis and arteriosclerosis arearteriosclerosis, acute myocardial infarction, chronic stable angina,unstable angina, transient ischemic attacks, strokes, peripheralvascular disease, arterial thrombosis, preeclampsia, embolism,restenosis or abrupt closure following angioplasty, carotidendarterectomy, or anastomosis of vascular grafts.
 28. The methodaccording to claim 15, wherein said chronic or acute states ofhyper-aggregability is caused by DIC, septicemia, surgical or infectiousshock, post-operative and post-partum trauma, cardiopulmonary bypasssurgery, incompatible blood transfusion, abruptio placenta, thromboticthrombocytopenic purpura, snake venom or immune diseases.
 29. The methodaccording to claim 15, wherein said reocclusion of an artery or veinfollowing fibrinolytic therapy is inhibited by internal administrationof said compound with a fibrinolytic agent.
 30. The method according toclaim 29, wherein said fibrinolytic agent is selected from the groupconsisting of natural or synthetic products which directly or indirectlycause lysis of a fibrin clot.
 31. The method according to claim 29,wherein said fibrinolytic agent is a plasminogen activator selected fromthe group consisting of anistreplase, urokinase, pro-urokinase,streptokinase, tissue plasminogen activator and mutants or variantsthereof, which retain plasminogen activator activity.
 32. The methodaccording to claim 31, wherein said variants are selected from the groupconsisting of variants which have been chemically modified, variantswhich one or more amino acids have been added, deleted or substitutedand variants with one or more modified functional domains.
 33. Themethod according to claim 32, wherein said modified functional domainsare added, deleted or altered by combining the active site of oneplasminogen activator or fibrin binding domain with another plasminogenactivator or fibrin binding molecule.
 34. The pharmaceutical formulationaccording to claim 1, wherein said formulation is sterile.
 35. Thepharmaceutical formulation according to claim 1, wherein saidformulation further comprises a pharmaceutical carrier.
 36. Thepharmaceutical formulation according to claim 1, wherein saidformulation further comprises a buffering agent.
 37. A compound ofgeneral formula I, or salts thereof:

wherein: X₁, X₂, and X₃ are independently selected from the groupconsisting of oxygen, methylene, monochloromethylene, dichloromethylene,monofluoromethylene, difluoromethylene, and imido; T, W, and V areindependently oxygen or sulfur; m=0, 1 or 2; n=0, 1, or 2; p=0, 1, or 2;M=H or a pharmaceutically-acceptable inorganic or organic counterion;D₁=O or C; B′ is a purine or a pyrimidine residue according to generalformulas IV and V which is linked to the 1′ position of the furanose orcarbocycle via the 9- or 1-position, respectively; A is M or alkyl; or Ais a nucleoside residue which is defined as:

and which is linked to the phosphate chain via the 5′ position of thefuranose or carbocycle; wherein: D₂=O or C; B is a purine or apyrimidine residue according to general formulas IV and V which islinked to the sugar or carbocycle via the 9- or 1-position,respectively; wherein when D₁ and D₂ are oxygen, the furanose is in theβ-configuration; Y′=H, OH, or OR₁, where OR₁ falls under the definitionof general Formula II or III; Z′=OH or OR₂, where OR₂ falls under thedefinition of general Formula II or III; Z=OH or OR₃, where OR₃ fallsunder the definition of general Formula II or III; Y=H, OH, or OR₄,where OR₄ falls under the definition of general Formula II or III;provided that at least one of Y′, Z′, Z, and Y is OR₁, OR₂, OR₃, or OR₄,respectively; wherein compounds of general Formula I are molecules whosestructures fall within the definitions of Formula Ia and Formula Ib:

wherein: X₁, X₂, and X₃=O; T, V, and W=O; M=H, NH₄ ⁺, Na⁺ or otherpharmaceutically-acceptable inorganic or organic counterion; Y′=H, OH,or OR₁, where OR₁ falls under the definition of general formula II;Z′=OH or OR₂, where OR₂ falls under the definition of general formulaII; Z=OH or OR₃, where OR₃ falls under the definition of general formulaII; Y=H, OH, or OR₄, where OR₄ falls under the definition of generalformula II; provided that at least one of Y′, Z′, Z, and Y is OR₁, OR₂,OR₃, or OR₄, respectively; D₁=O; D₂=O or C; B and B′ are purine orpyrimidine residues according to general formulas IV and V; m and p=0, 1or 2; n=0 or 1; such that the sum of m+n+p is from 0 to 5; or X₁, X₂,and X₃=O; T, V, and W=O; M=H, NH₄ ⁺, Na⁺ or otherpharmaceutically-acceptable inorganic or organic counterion; D₁=O; Y′=H,OH, or OR₁, where OR₁ falls under the definition of general formula III;Z′=OH or OR₂, where OR₂ falls under the definition of general formulaIII; Z=OH or OR₃, where OR₃ falls under the definition of generalformula III; Y=H, OH, or OR₄, where OR₄ falls under the definition ofgeneral formula III; provided that at least one of Y′, Z′, Z, and Y isOR₁, OR₂, OR₃, or OR₄, respectively; D₂=O or C; B and B′ are purine orpyrimidine residues according to general formulas IV and V; m and p=0, 1or 2; n=0 or 1; such that the sum of m+n+p is from 0 to 5; or X₁ andX₃=O; X₂ is selected from the group consisting of methylene,monochloromethylene, dichloromethylene, monofluoromethylene,difluoromethylene, and imido; T, V, and W=O; M=H, NH₄ ⁺, Na⁺ or otherpharmaceutically-acceptable inorganic or organic counterion; Y′=H, OH,or OR₁, where OR₁ falls under the definition of general formula II;Z′=OH or OR₂, where OR₂ falls under the definition of general formulaII; Z=OH or OR₃, where OR₃ falls under the definition of general formulaII; Y=H, OH, or OR₄, where OR₄ falls under the definition of generalformula II; provided that at least one of Y′, Z′, Z, and Y is OR₁, OR₂,OR₃, or OR₄, respectively; D₁=O; D₂=O or C; B and B′ are purine orpyrimidine residues according to general formulas IV and V; m and p=0, 1or 2; n=1; such that the sum of m+n+p is from 0 to 5; or X₁ and X₃=O; X₂is selected from the group consisting of methylene, monochloromethylene,dichloromethylene, monofluoromethylene, difluoromethylene, and imido; T,V, and W=O; M=H, NH₄ ⁺, Na⁺ or other pharmaceutically-acceptableinorganic or organic counterion; Y′=H, OH, or OR₁, where OR₁ falls underthe definition of general formula III; Z′=OH or OR₂, where OR₂ fallsunder the definition of general formula III; Z=OH or OR₃, where OR₃falls under the definition of general formula III; Y=H, OH, or OR₄,where OR₄ falls under the definition of general formula III; providedthat at least one of Y′, Z′, Z, and Y is OR₁, OR₂, OR₃, or OR₄,respectively; D₁=O; D₂ is O or C; B and B′ are purine or pyrimidineresidues according to general formulas IV and V; m and p=0, 1 or 2; n=1;such that the sum of m+n+p is from 0 to 5; or X₁ and X₃=O; X₂ isselected from the group consisting of methylene, monochloromethylene,dichloromethylene, monofluoromethylene, difluoromethylene, and imido;T=S; V and W=O; M=H, NH₄ ⁺, Na⁺ or other pharmaceutically-acceptableinorganic or organic counterion; Y′=H, OH, or OR₁, where OR₁ falls underthe definition of general formula II; Z′=OH or OR₂, where OR₂ fallsunder the definition of general formula II; Z=OH or OR₃, where OR₃ fallsunder the definition of general formula II; Y=H, OH, or OR₄, where OR₄falls under the definition of general formula II; provided that at leastone of Y′, Z′, Z, and Y is OR₁, OR₂, OR₃, or OR₄, respectively; D₁=O;D₂=O or C; B and B′ are purine or pyrimidine residues according togeneral formulas IV and V; m, n and p=1; or X₁ and X₃=O; X₂ is selectedfrom the group consisting of methylene, monochloromethylene,dichloromethylene, monofluoromethylene, difluoromethylene, and imido;T=S; V and W=O; M is selected from the group consisting of H, NH₄ ⁺, Na⁺and other pharmaceutically-acceptable inorganic or organic counterion;Y′=H, OH, or OR₁, where OR₁ falls under the definition of generalformula III; Z′=OH or OR₂, where OR₂ falls under the definition ofgeneral formula III; Z=OH or OR₃, where OR₃ falls under the definitionof general formula III; Y=H, OH, or OR₄, where OR₄ falls under thedefinition of general formula III; provided that at least one of Y′, Z′,Z, and Y is OR₁, OR₂, OR₃, or OR₄, respectively; D₁=O; D₂=O or C; B andB′ are purine or pyrimidine residues according to general formulas IVand V; m, n, and p=1;

wherein: A is M or alkyl; X₁ and X₂=O; T, V, and W=O; M=H, NH₄ ⁺, Na⁺ orother pharmaceutically-acceptable inorganic or organic counterion; Y′=H,OH, or OR₁, where OR₁ falls under the definition of general formula II;Z′=H, OH or OR₂, where OR₂ falls under the definition of general formulaII; with the provision that at least one of Y′ and Z′ is OR₁ or OR₂;D₁=O or C; B′ is purine or pyrimidine residue according to generalformulas IV and V; n and p are 0, 1, or 2 such that the sum of n+p isfrom 1 to 3; or A is M or alkyl; X₁ and X₂=O; T, V, and W=O; M isselected from the group consisting of H, NH₄ ⁺, Na⁺ and otherpharmaceutically-acceptable inorganic or organic counterion; Y′=OR₁,where OR₁ falls under the definition of general formula III; Z′=OR₂,where OR₂ falls under the definition of general formula III; D₁=O or C;B′ is purine or pyrimidine residue according to general formulas IV andV; n and p are 0, 1, or 2 such that the sum of n+p is from 1 to 3; or Ais M or alkyl; X₁ and X₂=O; T and V=O; W=S; M=H, NH₄ ⁺, Na⁺ or otherpharmaceutically-acceptable inorganic or organic counterion; Y′=H, OH,or OR₁, where OR₁ falls under the definition of general formula II;Z′=H, OH or OR₂, where OR₂ falls under the definition of general formulaII; with the provision that at least one of Y′ and Z′ is OR₁ or OR₂;D₁=O or C; B′ is purine or pyrimidine residue according to generalformulas IV and V; p is 0, 1, or 2 such that the sum of n+p is from 1 to3; n=1; or A is M or alkyl; X₁ and X₂=O; T and V=O; W=S; M is selectedfrom the group consisting of H, NH₄ ⁺, Na⁺ and otherpharmaceutically-acceptable inorganic or organic counterion; Y′=OR₁,where OR₁ falls under the definition of general formula III; Z′=OR₂,where OR₂ falls under the definition of general formula III; D₁=O or C;B′ is purine or pyrimidine residue according to general formulas IV andV; p is 0, 1, or 2 such that the sum of n+p is from 1 to 3; n=1; or A isM or alkyl; X₁=O; X₂ is selected from the group consisting of methylene,monochloromethylene, dichloromethylene, monofluoromethylene,difluoromethylene, and imido; T, V, and W=O; M is selected from thegroup consisting of H, NH₄ ⁺, Na⁺ and other pharmaceutically-acceptableinorganic or organic counterion; Y′=H, OH, or OR₁, where OR₁ falls underthe definition of general formula II; Z′=H, OH or OR₂, where OR₂ fallsunder the definition of general formula II; with the provision that atleast one of Y′ and Z′ is OR₁ or OR₂; D₁=O or C; B′ is purine orpyrimidine residue according to general formulas IV and V; p is 0, 1, or2 such that the sum of n+p is from 1 to 3; n=1; or A is M or alkyl;X₁=O; X₂ is selected from the group consisting of methylene,monochloromethylene, dichloromethylene, monofluoromethylene,difluoromethylene, and imido; T, V, and W=O; M is selected from thegroup consisting of H, NH₄ ⁺, Na⁺ and other pharmaceutically-acceptableinorganic or organic counterion; Y′=H, OH, or OR₁, where OR₁ falls underthe definition of general formula III; Z′=H, OH or OR₂, where OR₂ fallsunder the definition of general formula III; D₁=O or C; B′ is purine orpyrimidine residue according to general formulas IV and V; p is 0, 1, or2 such that the sum of n+p is from 1 to 3; n=1; wherein, for compoundsaccording to Formula Ia or Ib, where Y′=OR₁, Z′=OR₂, Z=OR₃ and/or Y=OR₄,at least one of the four is a residue which is linked directly to thecorresponding 2′ or 3′ hydroxyl oxygen of the furanose or carbocycle viaa carbon atom; wherein said residue falls within the scope of formula IIor formula III:

wherein: O is the corresponding 2′ or 3′ oxygen of the furanose orcarbocycle; R₅, R₆, and R₇ are selected from the group consisting of H,an alkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl, andsubstituted aryl, such that the moiety defined according to formula IIis an ether; or R₅ and R₆ are taken together to be oxygen or sulfurdoubly bonded to Q, and R₇ is selected from the group consisting ofalkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl, ad substitutedaryl, such that the moiety defined according to formula II is an esteror thioester; or R₅ and R₆ are taken together to be oxygen or sulfurdoubly bonded to Q, and R₇ is amino or mono- or disubstituted amino,where the substituents are selected from the group consisting of alkyl,cycloalkyl, aralkyl, aryl, substituted aralkyl, and substituted aryl,such that the moiety according to formula II is a carbamate orthiocarbamate; or R₅ and R₆ are taken together to be oxygen or sulfurdoubly bonded to Q, and R₇ is selected from the group consisting ofalkoxy, cycloalkoxy, aralkyloxy, aryloxy, substituted aralkyloxy, andsubstituted aryloxy, such that the moiety according to formula II is acarbonate or thiocarbonate; or R₅ and R₆ are taken together to be oxygenor sulfur doubly bonded to Q and both the 2′ and 3′ oxygens of thefuranose are directly bound to Q to form a cyclical carbonate orthiocarbonate, R₇ is not present;

wherein: O is the 2′ and 3′ oxygens of the furanose or carbocycle; andthe 2′ and 3′ oxygens of the furanose or carbocycle are linked by acommon carbon atom to form a cyclical acetal, cyclical ketal, orcyclical orthoester; and for cyclical acetals and ketals, R₈ and R₉ areindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aralkyl, aryl, substituted aralkyl, and substituted aryl; orare joined together to form a homocyclic or heterocyclic ring composedof 3 to 8 atoms, or for cyclical orthoesters, R₈ is selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, aralkyl, aryl,substituted aralkyl, and substituted aryl, and R₉ is selected from thegroup consisting of alkyloxy, cycloalkyloxy, aralkyloxy, aryloxy,substituted aralkyloxy, and substituted aryloxy; B and B′ areindependently a purine residue, as in formula IV, linked through the9-position, or a pyrimidine residue, as in formula V, linked through the1-position; wherein, provided when D₁ and D₂ are oxygen, the ribosylmoieties are in the D-configuration;

wherein: R₁₀ and R₁₄ are selected from the group consisting ofalkylthio, alkyloxy, aryloxy, cycloalkylamino, aralkylamino, arylamino,diaralkylamino, and diarylamino, where the alkyl groups are optionallylinked to form a heterocycle; or R₁₀ and R₁₄ are acylamino according toFormula VI, provided that they incorporate an amino residue from the C-6position of the purine or the C-4 position of the pyrimidine; or whenR₁₀ in a purine or R₁₄ in a pyrimidine has as its first atom nitrogen,R₁₀ and R₁₁ or R₁₄ and R₁₅ are taken together to form a 5-membered fusedimidazole ring, optionally substituted on the etheno ring with R₅-R₉selected from the group consisting of alkyl, cycloalkyl, aralkyl, oraryl moieties, as described above; J is carbon or nitrogen, with theprovision that when nitrogen, R₁₂ is not present; R₁₁ is hydrogen, O oris absent; R₁₂ is selected from the group consisting of hydrogen, alkyl,azido, alkylamino, arylamino, aralkylamino, alkoxy, aryloxy, aralkyloxy,alkylthio, arythio, aralkylthio, and ω-A(C₁₋₆alkyl)B- wherein A and Bare selected from the group consisting of independently amino, mercapto,hydroxy and carboxyl; R₁₃ is selected from the group consisting ofhydrogen, chlorine, amino, monosubstituted amino, disubstituted amino,alkylthio, arylthio, and aralkylthio, where the substituent on sulfurcontains up to a maximum of 20 carbon atoms, with or withoutunsaturation; R₁₅ is selected from the group consisting of hydrogen, andacyl, such as acetyl, benzoyl, phenylacyl, with or without substituents;R₁₆ is selected from the group consisting of hydrogen, methyl, alkyl,halo, alkyl, alkenyl, substituted alkenyl, alkynyl, and substitutedalkynyl;

wherein: NH is the amino residue at the C-6 position in a purine or theamino residue at the C-4 position in a pyrimidine; Q is a carbon atom; Wis oxygen or sulfur; R₁₇ is amino or mono- or disubstituted amino suchthat the moiety according to formula VI is a urea or thiourea; or R₁₇ isselected from the group consisting of alkoxy, aralkyloxy, aryloxy,substituted aralkyloxy, and substituted aryloxy, such that the moietyaccording to formula VI is a carbamate or thiocarbamate; or R₁₇ isselected from the group consisting of alkyl, cycloalkyl, aralkyl, andaryl, with or without substituents or heteroatoms, such that the moietyaccording to formula VI is an amide.
 38. The pharmaceutical formulationof claim 1 wherein said compound is a compound of Formula I:

wherein: V=O; n=m=p=0; A=M; M=H or a pharmaceutically-acceptableinorganic or organic counterion; D₁=O;

wherein: O is the 2′ and 3′ oxygens of the furanose; and the 2′ and 3′oxygens of the furanose are linked by a common carbon atom to form acyclical acetal; and R₈ is hydrogen; and R₉ is selected from the groupconsisting of aralkyl, aryl, substituted aralkyl, and substituted aryl;in which the aralkyl groups are from 1 to 5 carbons in the alkylportion, and are: monocyclic moieties from 4 to 8 carbons withoutheteroatoms in the aryl portion; and the aryl groups are monocyclicmoieties from 4 to 8 carbons, without heteroatoms; B′ is a purineresidue according to general Formula IV wherein: R₁₀ is acylamino,according to Formula VI; W is oxygen; and R₁₇ is amino or mono- ordisubstituted amino such that the moiety according to Formula VI is aurea; J=carbon; R₁₁ is absent; R₁₂ is hydrogen; and R₁₃ is hydrogen.